In November 1860, Lincoln was elected as the sixteenth president of the United States. Secessionists again threatened to leave the Union. It was no empty threat. On 20 December 1860, the State of South Carolina was the first to declare itself a sovereign nation. The Confederate States of America was born. Other states soon followed, and by February 1861, Florida, Alabama, Mississippi, Georgia, Louisiana and Texas had also seceded.

As part of their Declaration of Causes of Secession, South Carolina cited the fourth article of the US Constitution:

No person held to service or labor in one State under the laws thereof, escaping into another, shall, in consequence of any law or regulation therein, be discharged from such service or labor, but shall be delivered up, on claim of the party to whom such service or labor may be due.

South Carolina saw the Constitution as a contract and blamed the North for violating it, declaring that such a pact was null and void if one party failed to meet their obligations. Once again, slavery was the issue that led to secession. But it was never a matter of the rights of the slaves themselves that created conflict, but the rights of those who owned the slaves.

A total of eleven slave states seceded from the Union. Eight other slave states gave consideration to the move, but for various reasons either could not or did not join the Confederacy. Missouri was one state that voted for secession, but was prevented from acting upon it when Lincoln declared martial law. The United States refused to recognize the Confederate States of America as a sovereign country and declared secession illegal. No European power ever officially recognized the sovereignty of the Confederacy but nonetheless they continued to trade with them. Only the Indian Territory and some Indian tribes aligned themselves with the Confederate States. In February 1861, Jefferson Davis was elected president of the Confederate States of America and would remain in the position throughout the war.

When Southern states began to secede, Union troops began to take possession of what defences they could. The troops, under the command of Major Robert Anderson, occupied Fort Moultrie in the harbour at Charleston, South Carolina. When South Carolina voted to secede, Anderson moved to nearby Fort Sumter, which was surrounded by water and commanded the entrance to Charleston Harbor, making it easier to defend. On 10 April 1861, Confederate forces under the command of Brigadier General Pierre Gustave Toutant Beauregard demanded that Anderson surrender. When no reply came, Beauregard began bombarding the fort. Three days later, on 13 April 1861, Major Anderson finally surrendered. The first engagement of the American Civil War was over, with no casualties resulting from the bombardment.

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