Beginning in the 1980s, various laboratories began to identify the specific molecular alterations in colorectal cancer (CRC), and the pace of discovery has continued unabated ever since. The breakthroughs began with the discovery of specific activating mutations of the KRAS oncogene in 19871 (and later, in BRAF2), followed by the concept of multistep carcinogenesis in 1988,3 the discovery of microsatellite instability (MSI) in 1992/1993,4,5 and later the CpG island methylator phenotype (CIMP) in 1999.