The design of clinical trials must evolve as new therapies become available. The demonstrated efficacy and clinical use of donepezil and vitamin E for Alzheimer disease (AD) has shifted the options for AD research design. There is now a compelling case for alternatives to trials that include a treatment arm with no active therapy (ie, a placebo control). With an existing therapy, such as donepezil or vitamin E, new drugs that are clearly superior to those drugs should be sought. Combination therapy is a likely strategy for the future, implying that clinical trials, if possible, should replicate actual practice. The long duration of future AD trials also will make placebo-controlled trials more difficult to justify and more difficult to recruit for. Add-on or active-control designs represent the alternative approaches. We believe that definitive clinical trials of new AD drugs that use one or the other of these designs would be more likely to bring about therapeutic advances than would comparisons with inactive treatments. Our argument is not a general rejection of placebo-control designs. Our recommendations apply only to the circumstances in which the field of AD drug therapy now finds itself.