Hepatocellular carcinoma accounts for approximately 700,000 deaths per year. This tumor displays morphologic and phenotypic heterogeneity, and heterogeneity extends to the molecular level. Nevertheless, common pathways have been identified that are variably employed by these tumors. Such pathways often include aberrant signaling by growth factors, many of which are involved in liver development and regeneration. This review focuses on several such pathways and highlights patterns of structural expression of relevant molecules as well as effects of pathway stimulation or inhibition, both in vitro and in vivo. Specifically, the HGF/MET axis, epidermal growth factor receptors and associated ligands, insulin growth factor, vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor and TGF-beta pathways are reviewed in the context of experimental models of HCC. Clinical-pathologic correlations are drawn for each of these, and current status of molecular targeted therapies is assessed. Review of available information indicates that redundancies and interactions among these signaling pathways must be taken into account if they are to be exploited to block and reverse HCC growth and spread.