Peer-review started: July 18, 2016
First decision: August 26, 2016
Revised: October 14, 2016
Accepted: November 21, 2016
Article in press: November 22, 2016
Published online: January 18, 2017
Processing time: 183 Days and 17.4 Hours
Core tip: The complete failure of chemotherapy in previous years gradually shifted hepatocellular carcinoma (HCC) treatment to the molecular targeted therapies. The initial-albeit limited - effectiveness of the currently approved systemic therapy, sorafenib, is due to the successful combination of targeting cancer cells and their microenvironment. Trials on drugs other than sorafenib, alone or in combination with drugs or transcatheter arterial chemoembolization were disappointing. Recently, genomic based analyses in HCC patients have proposed subclasses, based on molecular characteristics and a proliferative or non-proliferative genotypes. Combined targeted therapies, driven by specific molecular signatures for treatment selection and monitoring, potentially with immunotherapy, could be a future personalized approach.