Despite intensive laboratory and clinical research over three decades, an effective treatment to delay the onset and progression of Alzheimer’s disease is not at hand. Recent clinical trial failures suggest that we must treat the disease earlier than in its mild to moderate stages, and major progress in validating presymptomatic biomarkers now makes secondary prevention trials possible. We will learn more about the natural history of the disease and any partial therapeutic responses from detailed analyses of recent trial results. This process will likely position the field for success, but only with much greater investment in all aspects of Alzheimer research and with careful design of future trials.