The modern era of Alzheimer's disease (AD) research began in the early 1980s with the establishment of AD research centers and expanded research programs at the National Institute on Aging. Over the past 30 years, there has been success in defining criteria for AD and dementia, association of important genetic disorders related to premature dementia in families, the association of apolipoprotein-E(4), and measurement of incidence and prevalence and selected risk factors. However, prevention and treatment have been elusive. The development of new technologies, especially magnetic resonance imaging, positron emission tomography to measure amyloid in vivo in the brain and glucose metabolism, cerebrospinal fluid examination, better genetic markers, large-scale longitudinal epidemiology studies, and preventive clinical trials has rapidly begun a new era of research that offers opportunities to better understand etiology, that is, determinants of amyloid biology in the brain, neurofibrillary tangles, synaptic loss, and dementia. There are three major hypotheses related to dementia: amyloid deposition and secondary synaptic loss as a unique disease, vascular injury, and "aging." New research must be hypothesis-driven and lead to testable approaches for treatment and prevention. Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.