One reason for settlement is religious or other persecution. Minority groups feel threatened where they are and are unable to sustain themselves, so they move on to pastures new - often it is just because they want to live in a community of like-minded people.The Mormons, founded by Joseph Smith moved West, ultimately to Utah, because of this reason.
Early pioneers may have had only one doctor for hundreds of people, and no access to medicine once supplies ran out. The supply routes were an important factor as supply caravans or single couriers did not have as much protection from ambush and settlers were relying on them to return with news and supplies. Ignorance was another hazard.