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Of Mice and Men is a parable that tries to explain what it means to be human. His friend Ed Ricketts shaped Steinbeck's thinking about man's place in the universe. Essentially, man is a very small part of a very large universe; in the greater scheme of things, individuals come and go and leave very little, lasting mark. Yet deep inside all people is a longing for a place in nature — the desire for the land, roots, and a place to call "home." The struggle for such a place is universal, and its success is uncertain.
The significance of the title is in the futility of planning and the inevitablility of failure if the odds are stacked against you - as they are for George and Lennie. The novel is a condemnation of the American Dream, as has been said before but it also reflects on some of the principles of the American Constitution.