Our understanding of the molecular biology of colorectal cancer (CRC) has markedly improved over the past decade, and the “standard of care” for pathology departments now includes molecular testing of colorectal cancer samples in several situations. Microsatellite instable (MSI) colorectal cancers make up 15% of all cases, comprising 3% with Lynch Syndrome (Hereditary non-polyposis colorectal cancer) and 12% sporadic cases. MSI CRCs may be identified by molecular testing for microsatellite instability or immunohistochemistry for the mismatch repair proteins MLH1, PMS2, MSH2 and MHS6. The IHC profile and testing for BRAF V600E mutations assist in the distinction between sporadic MSI and Lynch syndrome cases. Targeted therapies against the MAP-Kinase pathway represent some of most exciting advances in cancer treatment in many decades. The response of metastatic colorectal cancer to anti-EGFR monoclonal antibody therapy is restricted to tumours with wild-type KRAS. Predicting response to targeted anti-cancer therapies is a major goal of molecular testing, and will rapidly evolve as new treatments become available. Next-generation sequencing and related technologies promise to revolutionize molecular diagnostics.