While advances have been made in understanding the neurobiological processes underlying Alzheimer's disease (AD), few treatment options currently exist. Numerous potential therapeutic and/or preventive agents have been tested in clinical trials, yet most have failed to show a clear therapeutic benefit. The lack of effective medical therapies coupled with the incipient projected dramatic increase in the number of persons with AD in the coming decades has put medical research in a crisis to urgently find effective treatment and prevention strategies. Researchers and funding agencies have been rethinking investigative approaches in order to accelerate scientific discovery in AD therapeutics, including methodological issues in the design and implementation of clinical trials. This review discusses lessons learned from discontinued and failed clinical trials for the treatment and prevention of AD with an emphasis on future directions of AD clinical trials. In particular, attention is given to choice of study outcome measures, participant selection and retention, and clinical trial design. While there are few treatments available for AD currently, the potential for discovery over the next decade is promising.