The design of clinical trials for hepatocellular carcinoma (HCC) is complex due to the concurrent liver disease, which can confound the assessment of clinical benefits. An expert panel convened by the American Association for the Study of Liver Diseases developed guidelines to standardize trial design, focusing on randomized phase 2 trials with time-to-event primary endpoints like time to progression. Survival remains the main endpoint in phase 3 studies, while time to recurrence is proposed for adjuvant settings. Composite endpoints like progression-free and disease-free survival are vulnerable and may not capture clinical benefits. The selection of the target population should be based on the Barcelona Clinic Liver Cancer (BCLC) staging system, with new drugs tested in patients with well-preserved liver function (Child-Pugh A class). Control arms should receive standard-of-care therapy, such as chemoembolization for intermediate-stage disease and sorafenib for advanced-stage disease. Further research is needed to incorporate biomarkers and molecular imaging into clinical trials to enrich study populations and maximize cost-benefit ratios. Phase 3 trials should be coordinated by centers with expertise in HCC.The design of clinical trials for hepatocellular carcinoma (HCC) is complex due to the concurrent liver disease, which can confound the assessment of clinical benefits. An expert panel convened by the American Association for the Study of Liver Diseases developed guidelines to standardize trial design, focusing on randomized phase 2 trials with time-to-event primary endpoints like time to progression. Survival remains the main endpoint in phase 3 studies, while time to recurrence is proposed for adjuvant settings. Composite endpoints like progression-free and disease-free survival are vulnerable and may not capture clinical benefits. The selection of the target population should be based on the Barcelona Clinic Liver Cancer (BCLC) staging system, with new drugs tested in patients with well-preserved liver function (Child-Pugh A class). Control arms should receive standard-of-care therapy, such as chemoembolization for intermediate-stage disease and sorafenib for advanced-stage disease. Further research is needed to incorporate biomarkers and molecular imaging into clinical trials to enrich study populations and maximize cost-benefit ratios. Phase 3 trials should be coordinated by centers with expertise in HCC.