In parallel with our growing understanding of the molecular pathways underlying colorectal neoplasia, significant advances have been made in the treatment of colorectal cancer (CRC). For the past few decades, 5-fluorouracil-based therapy has been the cornerstone of adjuvant therapy. More recently, additional cytotoxic drugs and molecular-targeted therapies have provided additional clinical benefit in certain patient populations. Unfortunately, overall survival remains about 45%. Notably, our understanding of why certain patients do or do not respond to treatment remains limited. Thus, as therapeutic options for CRC continue to expand, there is now an even greater imperative to identify reliable biomarkers that have the potential to predict prognosis as well as response to chemotherapy. In this review, we will summarize the current status of such molecular prognostic and predictive biomarkers in CRC and assess their usefulness in tailoring therapeutic options.