Both genetic and epigenetic factors contribute to the development of colorectal cancer. Specific genetic changes in proto-oncogenes, tumor suppressor genes, and DNA mismatch repair genes have led to a genetic model of colorectal tumorigenesis. Recent data highlight the importance of the TGF-beta signaling pathway in regulating the progression of colorectal cancer. The loss of the tumor suppressor activity of this pathway as well as the potentially cooperative genetic aberrations involving APC, K-ras, and p53 are reviewed in the context of the multi-step adenoma-carcinoma sequence that characterizes the development of colorectal tumorigenesis. In addition, contributing epigenetic factors including age, diet, angiogenesis, and immune response are also discussed. Combining our knowledge of the genetic and epigenetic events implicated in this disease may allow a broader understanding of the pathogenesis of colorectal cancer and hence the design of better anti-tumor interventions.