In evaluating disease changes, it is critical to have measurements that are sensitive, specific, and reliable. Cognitive decline, particularly in the context of Alzheimer's disease, is an area that has attracted numerous recent studies, and the proposed biomarkers used in these investigations need to be validated. In this review, we highlight studies with important implications about the role of imaging biomarkers in cognitive decline and dementia as well as in distinguishing preclinical dementia before evidence of cognitive decline. Structural changes determined on cross-sectional and longitudinal magnetic resonance imaging provide early prediction of dementia, particularly when combined with other measures. Molecular imaging using positron emission tomography and single photon emission computed tomography tracers quantify the presence or activity of receptors, transporters, enzymes, metabolic pathways, and proteins. The newest developments in molecular imaging are described, and methods are compared. Distinguishing features of imaging biomarkers among dementias and the spectrum of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease are described. Appropriate use criteria for positron emission tomography with amyloid tracers are delineated. Although these efforts are still in the early phase of development, there is great promise for further development in structural magnetic resonance imaging and positron emission tomography technologies.