This review summarizes the safety of sorafenib, an oral multikinase inhibitor, focusing on the randomized, placebo-controlled, Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) in renal cell carcinoma, which formed the basis of the approval of sorafenib. Similar to other targeted agents, sorafenib acts primarily to induce disease stabilization, rather than tumor regression, suggesting that long-term administration is necessary. The tolerability of an agent is important in long-term treatment, and a predictable and manageable side-effect profile is advantageous. Although IL-2 and interferon have been standard care treatments for advanced renal cell carcinoma for over a decade, they are poorly tolerated. Targeted agents offer an alternative for patients with advanced renal cell carcinoma, as initial therapy or after failure of cytokine treatment.