The systemic therapy landscape for hepatocellular carcinoma is rapidly evolving, as the recent approvals of checkpoint inhibitor-based regimens such as atezolizumab-bevacizumab and durvalumab-tremelimumab in advanced disease have led to an expanding therapeutic armamentarium. The development of biomarkers, however, has not kept up with the approvals of new agents. Nevertheless, biomarker research for hepatocellular carcinoma has recently been growing at a rapid pace. The most active areas of research are biomarkers for early detection and screening, accurate prognostication, and detection of minimal residual disease following curative intent therapies, and, perhaps most importantly, predictive markers to guide selection and sequencing of the individual agents, including tyrosine kinase inhibitors and immunotherapy. In this review, we briefly summarize the recent developments in systemic therapeutics for hepatocellular carcinoma, introduce the key completed and ongoing prospective and retrospective studies evaluating diagnostic, prognostic, and predictive biomarkers with high clinical relevance, highlight several potentially important areas of future research, and share our insights for each biomarker.