The prognosis of patients harboring metastatic colorectal cancer (CRC) remains poor despite therapeutic improvements obtained in recent years thanks to new biologic agents. A resistance mechanism limits the effectiveness of current cancer therapies to treat metastatic CRC patients. The identification of mechanisms of drug resistance may highlight new biomarkers useful to predict the clinical outcome or the likely responsiveness to pharmacological treatment of those metastatic CRC patients who cannot benefit from current therapeutic regimen. Moreover, the recognition of panels of biomarkers may suggest new strategies to overcome resistance by rational drug design and combination treatment. This review discusses CRC biomarkers, focusing initially on the most recent findings about the known ones, and mostly about the novel protagonists of this complex scenario.