Numerous signaling pathways, such as Ras/Raf/MAPK, have been implicated in hepatic carcinogenesis. There are at least 35 combination therapy studies for advanced stage hepatocellular carcinoma (HCC) ongoing, and numerous reagents are being tested targeting novel signaling cascades. The management of HCC has changed substantially in recent times, and the successful development of sorafenib has prompted further expansion on molecular targeted therapies to potentially inhibit different pathways in hepatocarcinogenesis.