Signaling pathways have become a major source of targets for novel therapies in 
hepatocellular carcinoma (HCC). Survival benefits achieved with sorafenib, a 
multikinase inhibitor, are unprecedented and underscore the importance of 
improving our understanding of how signaling networks interact in transformed 
cells. Numerous signaling modules are de-regulated in HCC, including some 
related to growth factor signaling (e.g., IGF, EGF, PDGF, FGF, HGF), cell 
differentiation (WNT, Hedgehog, Notch), and angiogenesis (VEGF). Intracellular 
mediators such as RAS and AKT/MTOR may also play a role in HCC development and 
progression. Different molecular mechanisms have been shown to induce aberrant 
pathway activation. These include point mutations, chromosomal aberrations, and 
epigenetically driven down-regulation. The use of novel molecular technologies 
such as next-generation sequencing in HCC research has enabled the 
identification of novel pathways previously underexplored in the HCC field, such 
as chromatin remodeling and autophagy. Considering recent failures of molecular 
therapies in advanced clinical trials (e.g., sunitinib, brivanib), survey of 
these and other new pathways may provide alternative therapeutic targets.