In delineating the molecular pathogenesis of hepatocellular carcinoma (HCC), recent experiments in mouse tumor models have revealed unexpected tumor-suppressing effects in genes previously identified as pro-oncogenic. This contradiction underscores the complexity of hepatocarcinogenesis and predicts uncertainty in targeting these molecules for HCC therapy. Deciphering the underlying mechanisms for these paradoxical functions will elucidate the complex molecular and cellular communications driving HCC development, and will also suggest more thoughtful therapeutic strategies for this deadly disease.