Epigenetic information is heritable during cell division but is not contained within the DNA sequence itself. Despite increasing evidence for and interest in the role of epigenetics in human disease, particularly in cancer, virtually no epigenetic information is routinely or systematically measured at the genome level. The current population-based approach to common disease relates common DNA sequence variants to either disease status or incremental quantitative traits contributing to disease. Although this purely genetic approach is powerful and general, there is currently no conceptual framework to integrate epigenetic information. In this article, we propose an approach to common human disease that incorporates epigenetic variation into genetic studies. Epigenetic variation might also help to explain the late onset and progressive nature of most common diseases, the quantitative nature of complex traits and the role of environment in disease development, which a purely sequence-based approach might not.