In 1999, the field of Alzheimer's disease (AD) therapeutics was turned on its head by reports that active immunization against amyloid β (Aβ) could reduce accumulation of Aβ plaques in brains of transgenic mice engineered to model AD pathology. These studies were rapidly followed by preclinical studies from multiple laboratories demonstrating efficacy of passive immunization with Aβ specific antibodies and in some cases, amelioration of cognitive deficits seen in AD mouse models. Such findings launched intensive and continuing efforts to develop Aβ immunotherapy as a safe and effective treatment for AD. In this issue of Biological Psychiatry, Sarazin et al. (1) summarize the current status of immunotherapy for Alzheimer's disease. They highlight the challenging side effects observed in the original active Aβ immunization trial and provide a summary of the disappointing results achieved in recent phase III trials of passive Aβ immunotherapy. Concerns that these trials failed because intervention occurred too late in the disease course have spurred new trial designs targeting asymptomatic familial AD carriers. As the authors point out, all such studies are entirely predicated on the amyloid hypothesis. Notwithstanding the applicability of this hypothesis, and therefore therapy, to nonfamilial cases of AD, this review points out a number of challenges related to designing preventative immunotherapy trials for sporadic AD and the classification of at-risk subjects. Because of these challenges, from a cynical point of view, the most informative outcome of immunotherapy trials in familial AD would be failure.