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Harriet's son Frederick enlisted in the Union army and almost immediately distinguished himself on the battlefield, winning a battlefield commission as lieutenant. In 1861, Agnes of Sorrento and The Pearl of Orr's Island were finally published in book form, and were successes.

As the war raged on, Harriet Beecher Stowe found herself disturbed by Britain's growing, if yet unofficial, diplomatic support of the Confederacy. She often flipped through a volume of twenty-six books she'd received as a gift during her first trip to England. The set was a collection of more than 560,000 signatures of British women–a petition against the institution of slavery, and delivered to Harriet as a gift with the name "Affectionate and Christian Address from the Women of Great Britain." It was a gift she had long cherished, but Britain's behavior now seemed a direct contradiction to these earlier sentiments. She wondered at the ongoing silence of Britain's once fervent female anti-slavery camp. Since Britain's diplomatic recognition of the Confederacy as a separate nation would be disastrous, Harriet felt she had to respond.

As Harriet worked on her reply, the war continued. On September 23, 1862, Lincoln signed the Emancipation Proclamation. Harriet would later call it one of the best days of her life. At Thanksgiving, Harriet went to Washington D.C. to join a thousand ex-slaves for a Thanksgiving dinner. The next day, she visited Abraham Lincoln, bringing along her young son Charles. This meeting elicited Lincoln's famous comment, "So this is the little lady who made this big war."

Harriet Beecher Stowe's response to Britain's position on the American Civil War was published in The Atlantic Monthly in January 1863, under the title "The Reply." Stowe, who either didn't grasp or ignored the complex political and economic reasons why Britain was tending towards diplomatic recognition of the Confederacy, blasted British women for keeping silent during the conflict, when previously they had been so vocal in their opposition against slavery. The rebuke was effective; even during the war, anything Harriet Beecher Stowe wrote was a bestseller, and any magazine with her byline sold out overnight. Lincoln would later attribute Britain's decision not to extend diplomatic relations to the Confederacy to three factors: Uncle Tom's Cabin, Harriet Beecher Stowe's "reply" to British women, and Henry Ward Beecher's speaking tour of England which took place during the height of the American conflict.

In the winter of 1863, Lyman Beecher died. That spring, Calvin Ellis Stowe retired from the Theological Seminary in Andover and his wife, against his wishes, bought a large, unfinished mansion in Hartford, Connecticut. Frederick was still serving in the Union army, and his parents worried about his safety incessantly. On July 1st, 1863, at the Battle of Gettysburg, Frederick was injured, suffering a blow to the head. His behavior became slightly erratic and he started drinking heavily. In the fall of 1863, Frederick was honorably discharged from the Union army, a decorated soldier. When he moved to Boston to study medicine, Harriet began receiving anonymous letters from strangers who had seen her son stumbling around the streets of Boston in a drunken stupor. Harriet, a teetotaler like her father, was crushed by these letters, but kept her pain very much to herself. She channeled her frustrations and sorrows into even more work. Between the years of 1863 and 1870, Harriet wrote ten books, including children's books and a four volume set of short biographies called Men of Our Times.

In 1865, the North won the war. Over 600,000 people were killed in the four years of civil war, and the South was in shambles. After the war, Harriet and Calvin decided to travel to Florida. The New England winters were increasingly hard on Calvin, who longed for a warm climate to spend the season. Everyone in Harriet's circle of friends warned her against traveling in the south, since she was so universally dislike there. She ignored her friends' warnings and made the trip. She was treated coldly by the Southerners she came in contact with, but was not harmed.

In 1866, in an attempt to reform her alcoholic son Frederick, she rented a Florida plantation for him to oversee, and hired one hundred ex-slaves. Within two years it was clear Frederick had no talent, and no will, to make the venture a success. In 1868, Harriet bought an orange farm in Mandarin, Florida and, again, encouraged Frederick to make a go of it. But he was so hopelessly dependent on alcohol that his family finally sent him to an institution.

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