Tumors are currently defined at the organ level and then further classified by pathological assessment and molecular analysis. However, these classification schemes do not necessarily reflect the biological makeup of tumors, which originate from a defined pool of cells-of-origin. The human body contains more than 100 cell types which are epigenetically programmed by DNA methylation. Of note, we and others have used genome-wide methylation profiling to show that cell type-specific DNA methylation patterns are maintained from the cancer cell-of-origin to the fully developed tumor and I will illustrate this approach using colorectal cancer and non-melanoma skin cancer as examples. Our findings provide an opportunity for the establishment of a biologically defined diagnostics scheme that classifies tumors according to their cell-of-origin.