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At the beginning of the war, the answer would be New Orleans.

After that fell, St. Louis and Memphis were both significant pressure-points.

Finally, the river-port of Vicksburg became the last Confederate stronghold on the river. For this reason, Jefferson Davis urged the garrison commander, Pemberton, to hold it at any cost, while the area commander Joe Johnston was urging Pemberton to evacuate the place and save his army.

U.S. Grant was able to exploit this confusion, and he took the surrender of Vicksburg on the Fourth of July 1863.

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