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.