Optimal treatment of hepatocellular carcinoma (HCC) is clinically challenging. Systemic treatment for advanced HCC was limited until the approval of sorafenib. This discovery resulted in the advent of many clinical trials. An ongoing Phase III trial is examining the benefit of adjuvant sorafenib. Utilization of doxorubicin-eluting bead embolization may offer safer treatment in eligible HCC patients. The use of systemic treatment peritransarterial chemoembolization is also being investigated. Many targeted therapies are being explored as first-/second-line treatment options in advanced HCC. The potential benefit of c-MET inhibitors, particularly in those with advanced, MET high expression HCC, may result in new systemic patient-directed targeted medicinal approaches. Remaining dilemmas query the appropriate management of patients with advanced Child–Pugh B, HCC and those recurring post-transplant.