The purpose of this review is to evaluate progress in molecular epidemiology over the past 24 years in cancer etiology and prevention to draw lessons for future research incorporating the new generation of biomarkers. Molecular epidemiology was introduced in the study of cancer in the early 1980s, with the expectation that it would help overcome some major limitations of epidemiology and facilitate cancer prevention. The expectation was that biomarkers would improve exposure assessment, document early changes preceding disease, and identify subgroups in the population with greater susceptibility to cancer, thereby increasing the ability of epidemiologic studies to identify causes and elucidate mechanisms in carcinogenesis. The first generation of biomarkers has indeed contributed to our understanding of risk and susceptibility related largely to genotoxic carcinogens. Consequently, interventions and policy changes have been mounted to reduce risk from several important environmental carcinogens. Several new and promising biomarkers are now becoming available for epidemiologic studies, thanks to the development of high-throughput technologies and theoretical advances in biology. These include toxicogenomics, alterations in gene methylation and gene expression, proteomics, and metabonomics, which allow large-scale studies, including discovery-oriented as well as hypothesis-testing investigations. However, most of these newer biomarkers have not been adequately validated, and their role in the causal paradigm is not clear. There is a need for their systematic validation using principles and criteria established over the past several decades in molecular cancer epidemiology.