Resmetirom, a liver-targeted thyroid hormone receptor-β selective drug, has been conditionally approved by the FDA for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced fibrosis. It has shown promising results in clinical trials, reducing hepatic fat content, improving liver histology, and ameliorating liver damage biomarkers without significant effects on body weight or glucose metabolism. Resmetirom also has favorable effects on circulating lipids, potentially reducing cardiovascular risk in MASH patients. Its safety profile is generally acceptable, with gastrointestinal adverse events being the most common, though long-term monitoring is needed for potential risks related to thyroid, gonadal, or bone diseases. Resmetirom's clinical implementation faces challenges in patient selection and monitoring treatment response, relying on non-invasive tests for liver fibrosis assessment. It represents a landmark breakthrough in MASH treatment, offering a new therapeutic strategy to mitigate the multifaceted risks of this complex metabolic liver disease. The drug has shown significant efficacy in reducing MRI-PDFF assessed hepatic fat content, improving liver fibrosis, and reducing serum liver enzymes and fibrosis biomarkers. It also demonstrates a significant beneficial effect on circulating lipids, including LDL cholesterol, triglycerides, and lipoprotein(a), which may reduce cardiovascular risk. Resmetirom has an acceptable safety profile, with no significant adverse events related to the cardiovascular system. However, long-term use may require monitoring for potential risks related to thyroid, gonadal, or bone diseases. The drug is recommended for patients with a BMI >100 kg. Resmetirom's use in adolescents is currently unknown. The drug's long-term safety and efficacy results from the ongoing MAESTRO-NASH trial will provide further insights. Resmetirom's availability opens new questions about how and when to define treatment response, with the need for simple, easily available tests for fibrosis to determine when to stop treatment. Resmetirom's potential as a treatment benchmark for future trials with other compounds being investigated for MASH treatment is also under consideration. The drug's role in the future treatment of non-cirrhotic MASH, particularly in early stages of the disease, and its impact on clinical events in compensated cirrhosis, as well as its use in combination with other therapies, remain key open questions. Overall, resmetirom represents a significant advancement in the treatment of MASH, offering a new therapeutic approach to address the complex metabolic liver disease.Resmetirom, a liver-targeted thyroid hormone receptor-β selective drug, has been conditionally approved by the FDA for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced fibrosis. It has shown promising results in clinical trials, reducing hepatic fat content, improving liver histology, and ameliorating liver damage biomarkers without significant effects on body weight or glucose metabolism. Resmetirom also has favorable effects on circulating lipids, potentially reducing cardiovascular risk in MASH patients. Its safety profile is generally acceptable, with gastrointestinal adverse events being the most common, though long-term monitoring is needed for potential risks related to thyroid, gonadal, or bone diseases. Resmetirom's clinical implementation faces challenges in patient selection and monitoring treatment response, relying on non-invasive tests for liver fibrosis assessment. It represents a landmark breakthrough in MASH treatment, offering a new therapeutic strategy to mitigate the multifaceted risks of this complex metabolic liver disease. The drug has shown significant efficacy in reducing MRI-PDFF assessed hepatic fat content, improving liver fibrosis, and reducing serum liver enzymes and fibrosis biomarkers. It also demonstrates a significant beneficial effect on circulating lipids, including LDL cholesterol, triglycerides, and lipoprotein(a), which may reduce cardiovascular risk. Resmetirom has an acceptable safety profile, with no significant adverse events related to the cardiovascular system. However, long-term use may require monitoring for potential risks related to thyroid, gonadal, or bone diseases. The drug is recommended for patients with a BMI >100 kg. Resmetirom's use in adolescents is currently unknown. The drug's long-term safety and efficacy results from the ongoing MAESTRO-NASH trial will provide further insights. Resmetirom's availability opens new questions about how and when to define treatment response, with the need for simple, easily available tests for fibrosis to determine when to stop treatment. Resmetirom's potential as a treatment benchmark for future trials with other compounds being investigated for MASH treatment is also under consideration. The drug's role in the future treatment of non-cirrhotic MASH, particularly in early stages of the disease, and its impact on clinical events in compensated cirrhosis, as well as its use in combination with other therapies, remain key open questions. Overall, resmetirom represents a significant advancement in the treatment of MASH, offering a new therapeutic approach to address the complex metabolic liver disease.