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For the first two years Confederate forces did well in set battles but lost control of the border states. The Confederates had the advantage of defending a very large country in an area where disease caused twice as many deaths as combat. The Union pursued a strategy of seizing the coastline, blockading the ports, and taking control of the river systems. By 1863 the Confederacy was being strangled. Its eastern armies fought well, but the western armies were defeated one after another until the Union forces captured New Orleans in 1862 along with the Tennessee River. In the famous Vicksburg Campaign of 1862–63, Ulysses Grant seized the Mississippi River and cut off the Southwest. Grant took command of Union forces in 1864 and after a series of battles with very heavy casualties, he had Lee under siege in Richmond as William T. Sherman captured Atlanta and marched through Georgia and the Carolinas. The Confederate capital was abandoned in April 1865 and Lee subsequently surrendered his army at Appomattox Court House; all other Confederate armies surrendered within a few months.

Who took control of the Mississippi River in 1862-63?
Ulysses Grant