In Wolfe's context
it was in reference to the hero coming home just after he wrote an acclaimed novel about his hometown. But he was afraid of the town's reaction, as he exposed the positives and negatives. Somewhere along the line, our hero runs into a man from his hometown who is not well-liked by the townfolk. The man used to be loved but now, our hero's been told, he's turned evil. As it turns out, when our hero sits and talks to the man, he finds out the guy's been misrepresented. That's when the guy turns to him and says, "You can't go home again."
Sorry about the vagueness of this explanation, but I'm away from my bookshelves right now. When I get home, I'll post the exact details. But the idea, as Levi pointed out, is that time doesn't stand still and neither should the way people think and live.