While we may not be able to find a cure for Alzheimer's disease (AD) in the near future, several drugs presently in trials have shown promise as possible modifiers of disease progression. However, we may not be able to demonstrate efficacy due to issues of recruitment, retention, site-to-site variability, and other methodological issues. It is thus incumbent on the scientific community to find solutions to these problems, particularly as the field moves toward preventing illness or treating the disease in its prodromal stages, where these methodological issues will become even more critical. We need to better understand why participants agree or refuse to enter drug trials, and why both primary care physicians and Alzheimer's specialists agree or refuse to involve their patients. We also need to quantify the impact of requiring imaging studies, extensive questionnaires, cognitive testing, and lumbar punctures on recruitment and retention. With these concerns in mind, an international task force meeting of experts from academia and industry in the United States, European Union, and Japan in San Diego, California on November 2, 2011 to focus on recruitment, retention and other methodological issues related to clinical trials for AD. Based on the recommendations of this Task force meeting, this Perspectives article critically reflects on the most critical and timely methodological issues related to recruitment and retention in prevention and therapeutic trials in AD, which are paralleled by a paradigm shift in the diagnostic conceptualization of this disease, as reflected by recently new proposed diagnostic criteria involving preclinical stages of the disease.