Hepatocellular carcinoma (HCC) is the fifth most common cancer and one of the leading causes of cancer death worldwide. Hepatocarcinogenesis is a multistep process developing from normal through chronic hepatitis/cirrhosis and dysplastic nodules to HCC. Although we have insufficient understanding to propose a robust general model, with advances in molecular methods, there is a growing understanding of the molecular mechanisms in the development of HCC. Hepatocarcinogenesis is strongly linked to increases in allelic losses, chromosomal changes, gene mutations, epigenetic alterations, and alterations in molecular cellular pathways. Special emphasis in this review is given to the genetics, epigenetics, and regulation of major signaling pathways involved in HCC such as Wnt/b-catenin, Ras, and PI3K/Akt/mTOR pathways. A detailed understanding of the underlying molecular mechanisms involved in the progression of HCC can improve our prevention and diagnostic tools for HCC and be an important potential source of novel molecular targets for new therapies.