The completion of the human genome project has marked a new beginning in biomedical sciences. Human cancer is a genetic disease and, accordingly, the field of oncology has been one of the first to be impacted by this historic revolution. Knowledge of the sequence and organization of the human genome facilitates the systematic analysis of the genetic alterations underlying the origin and evolution of tumors. Recent mutational analyses in colorectal and other cancers have focused on examination of gene families involved in signal transduction, such as kinases and phosphatases. This approach has been successful in identifying mutations in a variety of different genes, including the identification of PI3KCA as one of the most commonly mutated oncogenes in human cancer. Such genomic analyses have already demonstrated their utility in basic and clinical cancer research, and are expected to have an important impact on future diagnostic and therapeutic strategies.