Recent improvements in our understanding of the biology of colorectal cancer have led to the identification of several important prognostic and predictive markers of disease-associated risk and treatment response for the individual patient. Proper utilization of these biomarkers can enable physicians to tailor therapeutic strategies to maximize the likelihood of response and minimize treatment toxicity. In the management of colorectal cancer, tremendous progress has been made in the development of strategies for immune checkpoint inhibition; in refinement of agents and approaches used in targeted therapy; and in techniques for molecular subtyping of tumor samples that have identified patient subgroups with clinically relevant cellular differences potentially affecting clinical management and treatment outcome. In this article, we discuss several of the commonly tested markers in colorectal cancer-including microsatellite instability, RAS/RAF, DPD, HER2, UTG1A1, TS, and Immunoscore-and highlight their prevalence, prognostic and predictive value, and current role in the overall treatment paradigm.