Hepatocellular carcinomas (HCCs) are characterised by considerable phenotypic 
and molecular heterogeneity. Treating HCC and designing clinical trials are 
particularly challenging because co-existing liver disease, present in most 
patients, limits aggressive therapeutic options. Positive results in recent 
phase III clinical trials have confirmed the high value of anti-angiogenic 
therapies for HCC in both first (sorafenib and lenvatinib) and second line 
(regorafenib and cabozantinib) treatment modalities. However, failure of several 
large randomised controlled clinical trials over the last 10 years underlines 
the necessity for innovative treatment strategies and implementation of 
translational findings to overcome the unmet clinical need. Furthermore, the 
promising results from novel immunotherapies are likely to complement the 
landscape of active compounds for HCC and will require a completely different 
approach to patients, as well as the development of prognostic/predictive 
biomarkers. Given our increasing understanding of the most abundant molecular 
alterations in HCC, effective enrichment of patients based on clinical and 
molecular biomarkers, as well as adaptive clinical trials, are now feasible and 
should be implemented. Herein, we aim to review important aspects of precision 
medicine approaches in HCC that might contribute to improving the molecular 
subclassification of patients in a clinical trial setting and pave the way for 
novel therapeutic strategies.