The antiangiogenic multikinase inhibitor sorafenib was the first systemic agent to demonstrate a significant improvement in the overall survival of patients with advanced hepatocellular carcinoma (HCC), thereby introducing molecularly-targeted therapy in a therapeutic field of unmet needs. However, survival benefits for patients on sorafenib treatment are modest in clinical practice and advancing the field is far more challenging than initially anticipated. Molecular and clinical heterogeneity diminishes signals of potential activity in unselected populations, and underlying liver cirrhosis seals the fate of many novel targeted agents by causing relevant toxicity and mortality. The failure of subsequent randomized controlled phase III trials underscores the urgent need to identify the driver targets and to develop matched active agents with manageable toxicities in specific phase I studies in patients with cirrhosis. Refinement of phase II-III trial designs with a biomarker-enriched patient-selection process and stratification according to prognostic baseline factors is indispensable to prevent another 5-year vain endeavour in systemic therapy of HCC.