Colorectal cancer is among the most common cancers affecting the western world. By the age of 70 yr, at least 50% of the Western population will develop some form of colorectal tumor, spanning the spectrum from an early benign polyp to an invasive adenocarcinoma. It is estimated that approximately 10% of the benign polypoid lesions will progress to invasive carcinoma. The concept that serial genetic changes are responsible for the transition from benign to neoplastic disease is not new. The description of hereditary cancers and the demonstration of carcinogenic substances inducing DNA damage have provided the foundation for the field of molecular oncology. During the past three decades, our understanding of how genetic alterations culminate in cancer has progressed rapidly, though the complete process has not been fully defined. The research to date has spanned many oncologic diseases, but has been especially well defined in colorectal cancer. The knowledge of the genetic alterations that result in colorectal cancer has important ramifications for future prevention, detection, and treatment of this disease.