Individualized tailored therapy is a currently pursuing direction for improving the outcome of patients with colorectal cancer. Targeted therapy is the potential strategy to reach this goal by evaluating status of the presumed targets and their related effector molecules and by maximizing the efficacy of chemotherapeutic agents with less toxicity in individual patient. Numerous hurdles should be overcome, however, because therapeutic outcome can be affected by multiple components; tumor characteristics such as somatic mutations at the DNA, RNA, and protein levels; patient characteristics like germline genetic polymorphisms in enzymes linked to drug metabolism; and environmental factors that include diet and physical activity. Currently, large numbers of potential biomarkers have been proposed but have not yet accomplished supporting evidences for their routine usage in clinics. Therefore, clinical trials driven by molecular targets and relevant biomarkers for the understanding of the conflicting data are needed to make markers available in clinical practice.