Grant carefully followed the deepening rift slavery caused in the United States over the 1850s. His friends remember often finding him in his office or his store lost in thought with a newspaper in his hand. While he seldom expressed his own opinions on the issue–as he remained characteristically cold and private in public–his friends gradually realized that he was "deeply pained" by the troubles. Grant's own politics stood somewhere in the middle: no longer beholden to the Democratic in-laws, he briefly adopted his father's Know- Nothing affiliation before settling as a Whig. He voted for the first time in the 1856 Presidential election, casting his ballot for James Buchanan.

When war erupted in the spring of 1861, Grant was able to predict its course with impressive accuracy. He predicted South Carolina's secession a week before it occurred, and predicted the secession of several other states later. Furthermore, his military training allowed him to guess the war would break out beginning at Fort Sumter in South Carolina. As President Abraham Lincoln issued a call for 75,000 troops, Grant became active in enlisting men in Galena. He refused a chance to be their captain, however, seeing such a command of volunteers as a demotion for a West Point-trained Captain. Grant instead offered his services to help train soldiers at Camp Yates in Illinois, but he was unable to gain the colonelcy that he so badly desired. He sent a letter to Washington volunteering his services, but never received an answer–the letter itself was not located until after the war ended. Even Grant's junior West Point classmate Major General George B. McClellan refused to meet with him. Finally, with the help of some local politicians, Grant succeeded. On June 17, 1861, he wrote to Julia, "You have probably seen that I have been appointed to a colonelcy?"

Colonel Grant set out for Missouri as commander of the Twenty-First Illinois Regiment. Missouri was a mess, its loyalties split between North and South, slave and free. The North considered the maintenance of Missouri as a free state critical to the Union's cause, and Grant for the most part stood as the key defender. He met little organized resistance and gave his volunteers a crash- course on military discipline, tactics, and training. On July 31, 1861, Lincoln submitted Grant's name to Congress for a promotion to brigadier general. Among Grant's cheerier moments that summer was a time when he dropped in on the rent collectors' office in St. Louis where he had worked in the late 1850s. His former partner cursed at him and tried to throw him out of the shop, but Grant now stood as a general of the Army. Meanwhile, Lincoln had already begun a shift of generals that would continue through the war, replacing Grant's commander with another unknown. Luckily, Grant was not "discovered" for several more months, giving him valuable time to learn his trade. He established a headquarters at Cairo, Illinois, and went to work. On November 7, 1861, he attacked the Confederate forces at Belmont, Missouri–an assault that was poorly planned and executed. Confederate reinforcements compelled Grant to retreat; he still had much to learn.

After a winter of logistics and politicking, Grant stood ready to lead the first foray into Confederate territory in the western theater. On February 3, 1862, General Henry W. Halleck, Grant's superior, authorized him to move against two forts in northern Tennessee. These two outposts, Fort Donelson and Fort Henry, were the two Confederate positions guarding the Cumberland and Tennessee rivers. With 17,000 men–Grant boasted to his sister that he now commanded more men than Winfield Scott had in Mexico–and a flotilla of gunboats, Grant moved on Fort Henry on February 6, 1862. After two hours of shelling, the Confederate commander sent his 2,500 troops away to Fort Donelson and surrendered the fort's staff of seventy men. The first battle had been primarily won by the Navy's ironclads, but the second would be Grant's alone. Two days later, after horrible bone-chilling weather, he set out for Donelson.

On February 14, 1862, Grant attacked. Confederate guns rendered the Union ironclads useless, and then Confederate counterattacks damaged the Union lines. Grant nonetheless asserted command, and he had a larger army with which to fight. Two days later, the Confederate commander, Brigadier General Simon B. Buckner–an old friend of Grant's–asked for a truce and terms of surrender, expecting to be granted leniency because of his old relationship with the General. Grant replied tersely: "No terms except an unconditional and immediate surrender can be accepted." Buckner relented to the "ungenerous and unchivalrous terms," surrendering more than 12,000 troops.

The capture of Forts Henry and Donelson–the first major Union victories in the war–opened up Tennessee to the Federal armies, and, perhaps more important, constituted a major victory for the Union morale. Ulysses S. Grant overnight became known across the nation as "Unconditional Surrender" Grant. Lincoln made him Major General of Volunteers. For once, it seemed that Grant's luck might be turning around.

For the next month, Grant and Halleck tried to outmaneuver each other in the political field of battle, as Halleck had become increasingly jealous of Grant's fame. Halleck had hoped for complete control of the western theater, but it became clear that in Grant he had a strong rival. Lincoln put a quick stop to the gamesmanship and rebuked Halleck, while at the same time giving him the western command.

In April 1862, Grant faced one of the biggest disasters of his military career. Confederate forces broke through an unfortified portion of the Union line early in the morning near the Shiloh meetinghouse in Tennessee. Confederate General Albert S. Johnson hoped to push the Union troops into the marshes to the north, where the Union army would be trapped. It almost worked, as the Union troops were caught unawares in their tents or at breakfast; it took Grant most of the day to reorganize a defense. In the area that came to be known as the "Hornet's Nest," a detachment of troops fought desperately to prevent a complete rout. At a critical hour, General Don Carlos Buell arrived with more Union troops and helped to push back the Confederates. After a sleepless night, Grant ordered his troops to counterattack at dawn. In horrendously bloody fighting, the Union troops began to recapture the camps lost the day before. However, Grant's men lacked the energy to pursue and finish off the enemy army, as they had lost too many of their own in the battle. The day's final toll shocked everyone. Two thousand of Buell's troops fell dead or wounded the second day alone. In fact, more men died–3,477–in the two-day battle of Shiloh than had died in any of America's previous wars: the Revolutionary War, the War of 1812, or the Mexican War.

While the newspapers and Union leadership proclaimed a huge victory, Grant realized for the first time the true terror war brings. Halleck moved Grant out of the command of the Army of Tennessee, instead moving him into the meaningless position of second-in-command of the western theater. The Union armies slowly moved through Tennessee through the rest of the summer, and Grant's former army remained in Memphis. Lincoln, though, reconsidered the decision to remove Grant as he looked at the state of the war at the end of the summer of 1862. The Union was largely losing of the war, while most of the major Union victories had belonged to Grant. Lincoln had been shuffling generals almost constantly, hoping one would win the war. He decided Grant should return to the Army of Tennessee. In Lincoln's words, "I cannot spare this man, he fights."

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