The field of clinical trials and therapeutics in Alzheimer disease (AD) is little more than 20 years old. Considerable progress has been made in crafting appropriate designs for clinical trials of promising therapeutic agents for AD. This article reviews basic issues in diagnostic criteria, choice of outcome measures, duration of trials and analytic strategies. Through trial and error, a general set of strategies has evolved for the assessment of putative therapies for mild to moderate AD. The experience of the past 2 decades has set the stage for discovering the next generation of anti-AD drugs and introducing those therapies at milder stages of the disease.