The death of a culture
The primary meaning of this novel is Dan's own agenda. He feels that he is in the final twilight of his life, and as he approaches death, he remembers his culture, and he remembers the beauty of what used to be. Having travelled, he understands his Native culture in light of many other human cultures, and he treasures it, but as he approaches death, so does his beautiful culture approach its own death. This book is Dan's efforts (with Kent of course) to save that culture, or at least to preserve it for a time.
The value of all human life
Just because the Native Americans considered themselves a part of nature, like an animal, the white Europeans began a history of oppressing them, abusing them, and then, when the Natives were forced to violence, blaming them for the conflict.
Dan maintains that all Native American lives are fully real, human lives that deserve the same rights and respect as all the other kinds. It just happens to be that these Native people have a wonderful, beautiful tradition that is tied to the very land. He worries that when history progresses, white people's versions of the stories will be the only ones to survive. Therefore this book is an act of faith, to ensure that the human stories of the Lakota tribe are not forgotten.
Social dysfunction on reservations
There are many issues on reservations, many of them similar in kind to other kinds of racial segregation. Not only did the European Americans eliminate most of the Native populations, they also oppressed them brutally and relegated them to these reservations to fend for themselves in many respects. There are some upsides to reservation life, but mostly, it is dysfunctional, and the culture did not survive the tradition for very long.