Hepatocellular carcinoma (HCC) is a heterogeneous tumor with many factors implicated in its development, with chronic infection and cirrhosis by hepatitis B virus (HBV) being the most prevalent. Cirrhosis due to metabolic syndrome, alcohol consumption, viral infection with hepatitis C virus (HCV) is also involved in its development. Treatment of HCC remains unsatisfactory. Therapeutic management for HCC includes liver transplantation, liver resection, ablation, chemoembolization, which depend on the tumor stage, liver function, and patient performance status. The involvement of different signaling pathways in the initiation and modulation of HCC development based on clinical and research data provided a strong rationale for the development of anti-cancer agents targeting key components of the pathways. The complexity of the tumor prevents the major goal of this therapeutic approach, since sorafenib, a multi-kinase inhibitor, is the only successful drug so far that belongs to the target directed therapy in advanced stage HCC.