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Treatment options for colorectal cancer have increased substantially in the past decade, with the introduction of novel biological therapies targeting cancer-specific molecules leading to significantly improved outcomes. Despite access to these treatments, we are not yet in an era where we can fully personalize treatment choices for patients with colorectal cancer. A number of prognostic and predictive markers have been identified that appear to be directly related to sensitivity to targeted therapies, such as those against epidermal growth factor receptor. However, the sensitivities of individual tumors toward different biological agents appear to be more complex. It seems that a more complete molecular signature of the tumor must be taken into account when making individual treatment choices. In the absence of having fully elucidated the influence of these prognostic or predictive markers, other surrogate markers of early treatment success may be useful in determining whether to continue treatment with a particular agent. In this review, we discuss the role of molecular markers in choosing appropriate treatment for the individual patient, along with the use of measuring the depth of response to a particular agent to assist decisions on whether to continue therapy in colorectal cancer.