Abstract Personalized cancer medicine is becoming increasingly important in colorectal cancer treatment. Especially for targeted therapies, large variations between individual treatment responses exist. Predicting therapy response is of utmost significance, as it prevents overtreatment and adverse effects in patients. For EGFR-targeted therapy, many mechanisms of resistance have been uncovered, for example, mutations in KRAS and BRAF, and upregulation of alternative receptors. Currently, routine testing for all known modifiers of response is unpractical, and as a result, decision-making for anti-EGFR therapy is still largely based on assessing the mutation status of an individual gene (KRAS). Recently, comprehensive classifications of colorectal cancer have been presented that integrate many of the (epi-)genetic and microenvironmental factors that contribute to colorectal cancer heterogeneity. These classification systems are not only of prognostic value but also predict therapy efficacy, including the response to anti-EGFR agents. Therefore, molecular subtype–based stratification to guide therapeutic decisions is a promising new strategy that might overcome the shortcomings of single gene testing in colorectal cancer as well as in other malignancies. Furthermore, the development of new agents in a disease subtype–specific fashion has the potential to transform drug-discovery studies and generate novel, more effective therapies. Cancer Res; 75(2); 245–9. ©2014 AACR.