Personalized/individualized/tailored therapy for each patient is an important goal for improving the outcome of patients with colorectal adenocarcinoma and includes the intention to maximize efficacy and minimize toxicity of chemotherapeutic agents. Numerous barriers must be overcome to reach this goal because outcome is affected by an unholy trinity of tumor characteristics that include somatic alterations at the DNA, RNA, and protein level; patient characteristics that include germline genetic differences such as polymorphisms in enzymes affecting the metabolism of chemotherapeutic agents; and environmental exposures and factors that include diet and physical activity. At present, evaluation of epidermal growth factor receptor (EGFR) expression by immunohistochemistry in colorectal adenocarcinoma is generally required for treatment with one of the monoclonal antibody therapies directed against that target, despite the absence of evidence for predictive value of the assay, whereas EGFR fluorescent in situ hybridization (FISH) may be predictive. In addition, the Food and Drug Administration of the United States now requires a 'black box' warning on the packaging of irinotecan for evaluation of germline polymorphism in UGT1A1, the gene mutated in Gilbert's syndrome, for potential reduction of drug dosage in patients with the UGT1A1*28 polymorphism. Numerous other potential markers have been identified but have not yet reached levels of evidence that support their routine usage. For example, KRAS gene mutation appears to preclude improved survival after therapy with monoclonal antibody therapy directed at EGFR, and extensive DNA methylation is associated with lack of efficacy of 5-fluorouracil (5-FU)-based chemotherapy. Additional markers will come into routine usage as reports of research studies continue to appear in the literature. Clinical trials driven by molecular targets and agents directed against them, and understanding of the conflicting data on utility of markers reported in the literature, are needed to advance the field.