Hepatocellular carcinoma (HCC) is the most prevalent primary hepatic cancer with high fatality and recurrence rates. The prognosis of advanced HCC is dismal, and treatment was limited for a decade to sorafenib with limited effectiveness and miserable overall survival. The advent of immune checkpoint inhibitors (ICPIs) provides a considerable step in the treatment of several advanced malignancies including HCC and opens new horizons for this group of patients. Two drugs belonging to ICPIs, namely nivolumab and pembrolizumab, have now been licensed by the US FDA as a second-line treatment of patients who have progressed or have not responded to sorafenib, both are inhibitors of programmed cell death protein 1 (PD-1). Possible synergism of ICPIs, when used in conjunction with drugs active against other checkpoint molecules, targeted drugs, and locoregional modalities, is now investigated in several clinical trials. The current challenge is to evolve predictive biomarkers of tumor response to appropriately select patients who may respond well to ICPIs.