If one theme can be thought of as defining the plot and symbolism of Of Mice and Men, that theme is loneliness. In many ways, from the outspoken to the subtle (such as Steinbeck's decision to set the novel near Soledad, California, a town name that means "solitude" in Spanish), the presence of loneliness defines the actions of the diverse characters in the book.
The itinerant farm worker of the Great Depression found it nearly impossible to establish a fixed home. These men were forced to wander from ranch to ranch seeking temporary employment, to live in bunk houses with strangers, and to suffer the abuses of arbitrary bosses. George sums up the misery of this situation at several points during his monologues to Lennie - "Guys like us, that work on ranches, are the loneliest guys in the world. They got no family. They don't belong no place" (15).
Of course, as George's monologue puts it, "With [George and Lennie] it ain't like that." He and Lennie have found companionship; they watch out for one another. And beyond that, they have a dream of finding a fixed place they could call home, a farm of their own. They are doing what they can to resist sinking into miserable loneliness, which seems to be the lot of so many other itinerant workers.
This dream, of course, does not come to fruition, and indeed Steinbeck seems to have designed his bleak world to preclude the possibility of escape from the cycles of loneliness and hollow companionship (whether found in drink, in prostitutes, in gambling) that come with financial hardship and dislocation.