Grant arrived in Washington to receive his new promotion on March 8, 1864. He then set about establishing a multi-theater campaign unlike anything yet attempted in the Civil War. Again, Grant's strategy revolved around continually killing Confederate soldiers–a brutal but effective plan. He knew he could wear down the enemy long before his own forces became depleted. In order for the strategy to work, however, he needed to keep up a constant pressure on the Confederate armies, who were under the command of Robert E. Lee. The western campaign had been hugely successful, cutting the Confederacy in two at the Mississippi River and reclaiming much of the land lost when the western states conceded. In the eastern theater, however, there had been little more than skirmishes for the better part of a year.

Grant thus started, knowing he started. He knew that he had the complete confidence of Lincoln. His own confidence never wavered. Grant urged General William T. Sherman toward Atlanta. He sent armies to Mobile, down the Shenandoah Valley, and one toward Richmond, the Confederate capital. Total war had begun. Grant stayed with General George Meade in northern Virginia, telling him, "Wherever Lee goes, there you will go also."

In May 1864, the assault began. Grant's troops entered the Wilderness on May 5–and some of the worst fighting America has ever seen. The cavalry of J.E.B. Stuart–the eyes and ears of Lee's army–were engaged south of the Wilderness, and Lee attacked without knowing the full size of the 120,000-strong army Grant commanded. Had Grant moved faster he might have been able to escape the battle, but the sheer size of his armies, supply trains, and support teams limited his mobility. The battle erupted in the dense rolling underbrush known as the Wilderness. Hundreds fell, then thousands, then tens of thousands. Brush fires erupted throughout the area and claimed as many men as bullets and shells did.

Unlike previous Union generals, Grant advanced after the bloody two days, and the two armies met again on May 8, 1864, at Spotsylvania Court House. Exhausted, both armies paused to set up defenses before the battle broke out on May 10. Lee won the battle after several continuous days of Union assaults failed to break the Confederate lines. Nonetheless, Grant was succeeding in his goal to wear down the Confederates. The Union still had reinforcements coming in, as new units arrived at Grant's post almost daily. The Confederates–already only half the size of the Union army to begin with–could expect no such reinforcements. They had exhausted their nation's manpower, and at this point it was only a matter of time. Grant was now so popular that he himself got twenty-two votes at the Republican convention to renominate Abraham Lincoln for the Presidency.

Grant continued his assault on Lee's army. However, the battle at Cold Harbor even gave Grant pause. Botched leadership, confusing orders, and strong Confederate fortifications exacted the second-worst toll of the war on the Union troops–6,000 Union men fell in a single hour of the battle. It was the only day of battle that Grant ever admitted regretting. However, the battle had not been a total waste–although in Grant's terms that was different from a defeat. Cold Harbor did not contribute to the success of the Army, but did result in the deaths of a number of Confederate troops, thus marking the battle at least a draw.

The Union Army did not stop. Grant began to search for a new opening through which to attack the Confederate Army, and he found it in small railroad town of Petersburg. His engineers secretly constructed a pontoon bridge across the James River, and all but a few corps of the army crossed behind Lee's lines to attack Petersburg. When a frontal assault again failed, Grant settled in for another siege. Time was still on his side. Failing to capture Petersburg by surprise, he settled down to a regular siege. From June 18, 1864, to April 2, 1865, the Army of the Potomac sat and waited outside Petersburg. Grant figured he could starve Lee out.

Meanwhile, the other Union armies were far from idle. General Philip Sheridan led a cavalry force through the Shenandoah Valley, destroying much of the fertile cropland in the area. Farther south, Sherman had begun his now-infamous march to the sea. He cut a miles-wide swath through Georgia, laying waste to everything in his army's path and ultimately capturing Savannah in December.

Petersburg fell in April 1865, and the final assault on the Confederate capital of Richmond began on April 3. As Union troops approached, the Confederate troops began to set fire to the city and withdraw. On April 7, 1865, Grant made his first peace overture to Lee. Lee responded with a question about the terms of surrender. For the first time in his military career, Grant actually offered some. He did not hear back from Lee until late on the night of April 8, when, after another day of fighting as Grant's armies drew a tighter noose around the remnants of Lee's forces, Lee proposed they meet to discuss the terms.

After a sleepless night, Grant declined the meeting and responded with an even more urgent request for surrender. Lee could play games no longer. He announced his intention to surrender, and Meade ordered a battlefield truce. The contrast between the two West Point men at the surrender could not have been greater. Lee arrived at the meeting in a full-dress uniform, while Grant wore nothing but his shabby field uniform. The two men shook hands, and Grant wrote out the terms of surrender he would accept: all officers must pledge their men would not take arms against the U.S. again, and they must surrender all equipment and supplies except for side-arms, privately-owned horses, and personal baggage. Lee thanked Grant for the "generous" terms, and mentioned that his cavalrymen and artillerymen would appreciate the use of their horses. Grant said that since the men would need those horses for planting and plowing, he would allow the beasts to be taken. Lee accepted. He mentioned his men were hungry after days on the run, and Grant ordered General Sherman's army to provide 25,000 rations. When Grant emerged from the house, cannons sounded to celebrate the victory. He immediately silenced them, saying that the Confederates were once again "our countrymen." Besides, Grant wrote that he felt "like anything rather than rejoicing." The war was over.

Five days later, John Wilkes Booth shot President Abraham Lincoln while he was attending a play at Ford's Theater.

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