A deeper understanding of hepatocellular carcinoma (HCC) and its microenvironment in the last over 10 years has led to the design and development of therapeutics which has finally made unprecedented clinical impact and improved survival outcomes. However we are only at the cusp of harnessing this new knowledge for even better treatment of HCC. Almost all systemic treatments for HCC are not biomarker driven. Only ramucirumab as second line therapy for HCC is guided by a biomarker – that of tumour marker AFP > 400 ng/mL. Of the multitargeting tyrosine kinase inhibitors, a common final pathway is anti-angiogenesis even as the respective drugs mechanistically target other molecular pathways also. Of the immune checkpoint inhibitors, no biomarkers currently drive decision making, particularly PDL1 expression on the tumour or immune microenvironment where immune checkpoint inhibitor treatments do not show preferential benefit of PDL1+ HCC. With the rise of more combination therapies beyond atezolizumab and bevacizumab, an omics classification and further understanding of the diverse subclasses of HCC could potentially inform for which patients would benefit most from the various treatments.