Recent advances in the molecular mechanisms of liver carcinogenesis, angiogenesis, tumor progression and metastasis provide an opportunity for identification of novel targets for therapy of hepatocellular carcinoma. This chapter will cover some of the newer potential molecules and pathways that are emerging as attractive candidates for targeted therapy of hepatocellular carcinoma. Preclinical and clinical studies on drugs targeting heparanase, heparan sulfate endosulfatase, proteasome, the cell death ligand TNF-related apoptosis- inducing ligand, the IGF pathway, glypican 3, Hedgehog, Myc, and the Wnt/β-catenin pathway are discussed.