Abstract: Sorafenib is a novel oral multikinase inhibitor that inhibits Raf kinase because of its anti-proliferative property. Sorafenib also inhibits receptor tyrosine kinases of multiple proangiogenic factors, such as VEGFR-1/2/3 and PDGFR-β. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. To date, sorafenib is the only approved systemic treatment for patients with hepatocellular carcinoma. The most common adverse events of this inhibitor included hand–foot skin reactions, nausea, diarrhea, weight loss, and hypertension. These adverse events can severely affect patient compliance, which may negate the effect of therapy. Correct understanding and treatment of these adverse events can improve clinical outcome. This paper discusses the clinical aspect of sorafenib-induced adverse events and the molecular basis behind their toxicity. Recommendations for the management of the adverse effects are also provided.