Multivitamin-multimineral (MVM) supplements are widely used in the United States, often in the hope of reducing the risk of cancer, cardiovascular disease, or other chronic disease. This article assesses the potential of randomized controlled trials and epidemiologic cohort studies for yielding reliable information on the effects of MVMs on chronic disease. A brief review of the available literature on MVMs in relation to incidence and mortality rates from prominent cancers and cardiovascular diseases is also provided along with a discussion of needed research. Specifically, the strengths and weaknesses of epidemiologic cohort studies and randomized controlled trials are summarized and discussed in the context of single-vitamin supplements when both types of studies are available. Recent review articles that include an assessment of MVMs in relation to cancer and cardiovascular disease are updated to provide a summary of available data. Few randomized controlled trials and few cohort studies of MVMs that are directly pertinent to cancer or cardiovascular disease are available. The data are not compelling concerning a role for MVMs in preventing cancer or cardiovascular disease morbidity or mortality, although some interesting leads merit further evaluation. Investigators responsible for cohort studies that assessed MVMs should be encouraged to report available data on MVMs and chronic disease. Depending in part on the results of such additional reports, a full-scale randomized controlled trial of well-selected MVMs in women may be warranted on public health grounds.