What was the greatest challenge faced by the first European settlers in America?

The native indians that were living on this land were one of the biggest threats to the European settelers. Including the risk of new diesese and lack of food and shelter.

The first settlers of Jamestown endured the problems of hostile Indians, starvation, and poor leadership and government. Jamestown was the second English Colony in the New World (Roanoke being the first) and the Indians attacked the settlers within 3 days of arrival in May of 1607.