Objective: To review systemic treatment options for patients with locally advanced unresectable hepatocellular carcinoma (HCC). Methods: Review of the literature. Results: The paradigm of what constitutes first-line treatment for advanced HCC is shifting. Until recently, many patients with advanced HCC were treated with repeated locoregional therapies, such as transartertial embolization (TACE). However, retrospective studies suggest that continuing TACE after refractoriness or failure may not be beneficial and may delay subsequent treatments because of deterioration of liver function or declines in performance status. With recent approvals of several systemic therapy options, including immunotherapy, it is vital to conduct a risk-benefit assessment prior to repeating TACE after failure, so that patients are not denied the use of available systemic therapeutic options due to declined performance status or organ function from these procedures. The optimal timing and the sequence of systemic and locoregional therapy must be carefully evaluated by a multidisciplinary team. Conclusion: Randomized clinical trials to improve patient selection and determine the proper sequence of treatments are needed. Given the heterogeneity of HCC, molecular profiling of the tumor to differentiate responders from nonresponders may elucidate potential biomarkers to effectively guide treatment recommendations.