Approved for the treatment of advanced renal cell carcinoma by the US FDA and other regulatory agencies, sorafenib is an agent with multiple targets that may also prove beneficial in other malignancies. Phase III trials are underway in melanoma, hepatocellular carcinoma and non-small-cell lung cancer. Scrutiny of the Phase II data and correlative studies conducted in that context suggests that inhibition of angiogenesis and signaling in tumor cells may play a part in the clinical efficacy of sorafenib. Although the vascular endothelial growth factor receptor inhibitors are the most populated class of targeted agents in cancer clinical trials, sorafenib may prove to have unique properties that distinguish it. A detailed discussion of the clinical trials in renal cell carcinoma, melanoma and hepatocellular carcinoma highlights what is known and what has yet to be understood about this agent.