Nostalgia
Much of the novel concerns Miles' flashbacks to better days. However, toward the end of the novel, he starts being honest about his own young life, reflecting on the mistakes of his parents. He is tempted throughout the novel to give into a "golden age" view of the past, even when the past had problems of its own. Nevertheless, nostalgia sets the tone for much of the novel, and perhaps it even might be at the root of Miles and Janine's divorce.
Hopelessness
Another problem in the novel is the lack of hope that small town life sometimes creates. This happens especially once businesses begin to close, like what's happening in Empire Falls. Miles is nervous about his business, his doomed marriage, and also the larger issues of life, like destiny and fate. The problem is that the external world has little hope to offer Miles. By the end of the novel, Miles comes very close to a breakthrough by being honest about his mother's affair (which he repressed for much of his life). Perhaps by facing the emotional challenge of honesty about his mother, Miles could reinvigorate his life and introduce the hope he desperately needs. The novel ends without showing whether he succeeds or fails.
Social conflict and small town drama
Another issue that Miles faces quite seriously is the small town drama that dominates Empire Falls. Instead of teaming together to figure out how to save the town, the townsmen devolve into personal politics, shown most clearly in the comical Walt Comeau whose relationship with Janine is barely worth envying. The pettiness of Janine's affair only underscores the boredom and burnout that Miles has felt for years. The small town life is not much fun when the town starts to slide into bankruptcy, and the fear brings out the worst in people, and since everyone knows everyone in Empire Falls, the small town has become a hellscape of conflict.