Hepatocellular carcinoma (HCC) stands as a major health problem worldwide. The management of advanced HCC, limited for a longtime by the disappointing results of conventional cytotoxic chemotherapies, has recently changed with the publication of the results of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, which demonstrated an overall survival benefit over placebo in patients with advanced HCC. This study was further confirmed by the Asian-Pacific trial using sorafenib in Eastern patients. Those trials demonstrated that therapeutic benefits may derive from improving our knowledge of deregulated signaling pathways involved in HCC carcinogenesis. This review summarizes the results of clinical trials in which targeted therapies are currently evaluated aiming to enlarge the therapeutic armamentarium for HCC in a near future.