Alzheimer's disease (AD) continues to be one of most difficult human diseases to treat. The past 18 months have been a cruel reminder of the challenges of finding new and effective treatments. In 2010, several large Phase III clinical trials were terminated for lack of therapeutic efficacy. Concurrently, an NIH expert review panel was resigned to conclude that there was insufficient scientific evidence to recommend any treatment choices for slowing the progression of AD. Why has this disease proved so daunting? The answer is complex. To begin, it is still not clear whether AD is one disease with a single cause or multiple syndromes with common symptoms and/or a common pathology. Resolving this question is a prerequisite for forecasting whether to expect a 'magic bullet' therapy or only incremental progress in select patient populations. This review will explore some of the details of recent clinical trials and consider some of the lessons learned. As therapies approach clinical trials, it is essential to understand the expectations of regulatory agencies such as the FDA and EMA to obtain approval. Lastly, we will cover some of the essential gaps in our scientific understanding about the disease process and the impact this has on target validation. The hope of finding of a quick cure for AD without a complete understanding of the disease may have been too optimistic. However, a prudent review of the scientific evidence, a clear understanding of the expectations of regulators, and careful attention to patient needs may still lead to good therapies in the foreseeable future.