It wasn't until his third voyage that Columbus actually reached the mainland, exploring the Orinoco River in present-day Venezuela.
And foods from the Americas, such as potatoes, tomatoes and corn, became staples for Europeans and helped increase their populations.
The Exchange also brought new diseases to both hemispheres, though the effects were greatest in the Americas.
A rescue party finally arrived, sent by the royal governor of Hispaniola in July, and Columbus and his men were taken back to Spain in November of 1504.
In the two remaining years of his life following his last voyage to the Americas, Columbus struggled to recover his lost titles.
Although he did regain some of his riches in May of 1505, his titles were never returned.