Simple SummaryHepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for approximately 85–90% of all cases of liver cancer worldwide. The five-year tumor recurrence rate has been estimated to be 70% among patients who present with resectable disease and undergo resection. Currently, there are no approved neoadjuvant (before surgery) or adjuvant therapies (after surgery) for these patients. This review summarizes the data from clinical trials that have evaluated systemic therapies’ safety and efficacy in the neoadjuvant and adjuvant setting for patients with resectable and potentially resectable disease.AbstractThe burden of hepatocellular carcinoma (HCC) continues to pose a significant global health problem. Several systemic therapies have recently been shown to improve survival for patients with unresectable disease. However, evidence to support the use of neoadjuvant or adjuvant systemic therapies in patients with resectable disease is limited, despite the high risk of recurrence. Neoadjuvant and adjuvant systemic therapies are being investigated for their potential to reduce recurrence after resection and improve overall survival. Our review identified various early-phase clinical trials showing impressive preliminary signals of pathologic complete response in resectable disease, and others suggesting that neoadjuvant therapies—particularly when combined with adjuvant strategies—may convert unresectable disease to resectable disease and cause significant tumor necrosis, potentially decreasing recurrence rates. The role of adjuvant therapies alone may also play a part in the management of these patients, particularly in reducing recurrence rates. Heterogeneity in trial design, therapies used, patient selection, and a scarcity of randomized phase III trials necessitate the cautious implementation of these treatment strategies. Future research is required to identify predictive biomarkers, optimize the timing and type of therapeutic combinations, and minimize treatment-related adverse effects, thereby personalizing and enhancing treatment strategies for patients with resectable and borderline resectable HCC.