What hardships did homesteaders face

Sickness took out a lot of homesteaders.
Bad weather could affect the growth of crops which was their way of making money.
Grasshoppers and other animals would also wipe out a whole field of crops which again was an issue
The possibility of being attacked by the Native Americans (Not all of them were hostile but it was still a threat. 
Stores were very rare, or very far away from your homestead, and so were medical supplies.