Hepatocellular carcinoma (HCC) is increasing in prevalence and has the potential to be a highly lethal malignancy. Patients with early-stage HCC have potentially curative therapeutic options, but treatments for more advanced HCC were limited until recently. Historically, tyrosine kinase inhibitors have been used in both the first- and second-line treatment of patients with advanced HCC; however, given HCC's highly immune-responsive origins, immunotherapy is proving to be a promising systemic therapy in the frontline as well as later lines of treatment. Notably, recent studies of the novel antibody therapy combination atezolizumab (anti-PD-L1) and bevacizumab demonstrated unprecedented, practice-changing efficacy in the advanced HCC setting and led to its Food and Drug Administration approval. Although such landmark studies offer new treatment options for patients with HCC, the role of potential biomarkers to monitor immunotherapy response is largely unknown and undergoing exploration.