Ten years of remarkable progress in understanding the fundamental biochemistry of Alzheimer's disease have been followed by ten years of remarkable and increasing clinical insight into the natural progression of the disorder. The concept of a long, intermediary, prodromal phase between the first appearance of amyloid plaques and tangles and the manifestation of dementia is now well established. The major challenge for the next decade is to chart the many cellular processes that underlie this phase and link the biochemical alterations to the clinical manifestation of Alzheimer's disease. We discuss here how genetics, new cell culture systems, and improved animal models will fuel this work. We anticipate that the resulting novel insights will provide a basis for further drug development for this terrible disease.