The molecular and genetic subtyping of cancer has allowed the emergence of individualized therapies. This approach could potentially deliver treatments that have both increased efficacy as well as reduced toxicity. A well-defined subtype of colorectal cancer (CRC) is characterized by a deficiency in the mismatch repair (MMR) pathway. MMR deficiency not only contributes to the pathogenesis of a large proportion of CRC, but also determines the response to many of the drugs that are frequently used to treat this disease. In this Review we describe the MMR deficient phenotype and discuss how a deficiency in this DNA repair process may impact on the management of CRC, including surgery, adjuvant chemotherapy and the choice of systemic agents for the palliation of advanced disease. We also discuss how the DNA repair defect in MMR deficient CRC could be exploited in the development of novel therapeutic strategies.