As a consequence of new innovative therapies and therapeutic combinations, the treatment of advanced colorectal cancer is becoming increasingly complex. Validated molecular biomarkers could contribute to patient management, but until recently, none has been routinely used. With the recognition that activating mutations of the KRAS oncogene can predict resistance to anti-epidermal growth factor receptor agents, the clinical value of biomarkers in advanced colorectal cancer has been brought to the fore. Prognostic and predictive biomarkers that reflect the molecular and therapeutic complexities of advanced colorectal cancer may provide valuable information regarding likely clinical outcome and therapeutic response and thus may improve patient management and therapeutic agent selection. Such biomarkers are discussed herein.