In 2012, the US Food and Drug Administration approved the kinase inhibitor regorafenib for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-,oxaliplatin-, and irinotecan-based chemotherapy; an anti-vascular endothelial growth factor therapy; and, if RAS wild-type, an anti-epidermal growth factor receptor therapy. This approval brought a much-needed noncytotoxic chemotherapy treatment alternative to this heavily pretreated patient population. Initial phase 3 randomized clinical trials established an overall survival benefit associated with regorafenib, an important outcome addressing an unmet need for these patients. Despite these clinical data, it remains unclear exactly how regorafenib exerts its clinical activity. Preclinical data have attributed multiple mechanisms of action to regorafenib; however, which of these are important to the clinical effects of regorafenib remains unclear. This insight into the multiple mechanisms of action of regorafenib in metastatic colorectal cancer has provided the basis for new clinical trials investigating novel combinations of this therapy.