Accumulated experimental evidence indicates that Hedgehog (Hh) signaling regulates cell proliferation and specification in a variety of organs during embryonic development. However, abnormal activation of this pathway in postnatal tissues has been linked to a large number of human cancers. With respect to the liver, it is known that Hh signaling not only influences bipotential precursor cells capable of pancreas and liver development, but is also implicated in the pathogenesis of liver tumors such as hepatoblastoma, hepatocellular and cholangiocellular carcinoma, if aberrantly activated. Blockade of Hh signaling by several specific inhibitors has been proven to successfully inhibit tumor growth of various Hh-associated cancers in vitro and in preclinical mouse models, and recent clinical data suggest that the implementation of novel anticancer therapeutics based on Hh interference into commonly accepted regimens are within reach. Thus, it is highly probable that Hh targeted therapies could be used for the treatment of Hh-dependent liver cancers in the future.