Background <p>Metabolic dysfunction and alcohol-associated steatotic liver disease (MetALD) has emerged as a new subtype of steatotic liver disease, and presents a substantial challenge in clinical trial design due to a lack of data and consensus on endpoint selection.</p> Objective <p>This review proposes patient selection, stratification, and optimization in Phase II and III clinical trial designs for MetALD and provides reasonable stage-specific clinical trial endpoints. It provides a comprehensive review of data on non-invasive tests (NITs) and trial endpoints in metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease, and extrapolates these data to MetALD.</p> Results <p>The design of effective MetALD trials necessitates rigorous stratification by fibrosis stage and drinking patterns. In pre-cirrhotic MetALD, NITs, including vibration-controlled transient elastography, magnetic resonance elastography, and magnetic resonance imaging-proton density fat fraction, are reliable surrogate endpoints, with each modality-specific cut-off set to meet clinical improvement targets. For patients with compensated or decompensated cirrhosis, the emphasis shifts to hard clinical outcomes, such as transplant-free survival, overall survival, and prevention of major adverse liver events in phase III clinical trials. Additionally, integrating alcohol-reduction endpoints and comprehensive cardiometabolic endpoints is essential to capture the full impact of interventions in clinical trials.</p> Conclusion <p>The MetALD clinical trials require strategic design, the adoption of the NITs shift concept, and stage- and phase-specific endpoints.</p>