<p>Metabolic dysfunction-associated steatotic liver disease (MASLD), a leading global cause of chronic liver disease, encompasses a wide spectrum of disease stages from isolated hepatic steatosis to cirrhosis. After decades of limited therapeutic options, pivotal developments, including the landmark FDA conditional approvals of resmetirom and semaglutide, mark a transformative era for metabolic dysfunction-associated steatohepatitis (MASH) management, with numerous additional promising treatments rapidly advancing through late-stage development. These milestones validate targeting both upstream metabolic dysfunction and intrahepatic injury, catalysing interest in rational combination strategies tailored to patient phenotype and disease stage. However, major challenges persist: the absence of dynamic, validated biomarkers of response; ongoing reliance on biopsy-based surrogates; high placebo response rates; and heterogeneity in disease biology and clinical course. Emerging approaches, such as noninvasive tests and multi-omic profiling, promise to refine patient selection, enrich trials and enable longitudinal monitoring at scale. This Review synthesizes lessons learned from prior trials and critically appraises current and emerging drug classes. We propose a pragmatic, mechanism-aligned framework for personalized MASH care that integrates lifestyle intervention, incretin-based therapies and liver-directed agents, with the overarching objective of mitigating progression to liver-related complications while simultaneously addressing the excess cardiometabolic morbidity and mortality that characterize this multisystem disorder.</p>