Cancer contributes to a large proportion of the mortality and morbidity in the United States and worldwide. Despite advances in diagnosis and treatment of various cancers, early detection and treatment of cancer remain a challenge. Diagnosis of cancer often occurs once the disease has progressed to a point where currently available intervention options provide limited success. Therefore, techniques that enable early detection followed by targeted interventions would influence stage at diagnosis and, in turn, mortality associated with cancer. Identification of molecular biomarkers, especially those that are associated with cancer initiation and progression, shows promise as an effective strategy in this regard. One potential early detection biomarker is DNA methylation of the promoter region of certain cancer-associated genes, which results in gene inactivation. Examination of serum for circulating tumor DNA with abnormal methylation patterns offers a possible method for early detection of several cancers and serves as a point for early intervention and prevention strategies. Additionally, it is imperative to consider how such a screening mechanism can be implemented in populations at risk, especially in resource-poor settings. Thus, the challenge is to validate DNA methylation as a cancer-specific biomarker, with the ultimate goal of designing a research plan that integrates the current knowledge base regarding cancer detection and diagnosis into specific prevention and intervention strategies that can be applied at a population level.