Sorafenib is an oral multikinase inhibitor that acts by inhibiting tumor growth and disrupting tumor microvasculature through antiproliferative, anti-angiogenic and proapoptotic effects. It exerts these effects via inhibition of multiple targets including Raf serine/threonine kinases, vascular endothelial growth factor receptor tyrosine kinases; VEGFR-1, VEGFR-2, VEGFR-3 and platelet-derived growth factor receptor β (PDGFR-β). Current literature shows that the deregulated signaling through these receptors is commonly seen in human tumors. In addition, sorafenib is also shown to induce apoptosis through downregulation of Mcl-1 in many cancer types. Hence, sorafenib as a single agent has shown promising activity in some cancers such as renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and thyroid cancers. Currently, the drug holds FDA approval for the treatment of advanced RCC and unresectable HCC. However, many clinical studies have indicated several limitations to the application of sorafenib as a single agent in various other cancers. Owing to these reasons and the potential of sorafenib to synergize with other anticancer therapies, its combination with other targeted agents and chemotherapy has been widely explored with promising results. In addition, it has also shown synergistic results when combined with radiation. This review summarizes the current basic and clinical studies on the effects and mechanisms of sorafenib either administered alone or in combination with other anticancer treatments.