The recent FDA approval of Rezdiffra (resmetirom), an oral partial agonist of the thyroid hormone receptor-beta (THR-beta), for the treatment of noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced fibrosis, has challenged conventional approaches to NASH drug development. Despite extensive efforts targeting typical pathways involved in NASH progression, such as lipogenesis, oxidative stress, and inflammation, these approaches have yet to yield any approved therapies. The success of resmetirom highlights the potential advantages of targeting THR-beta, which exerts pleiotropic effects on multiple pathways involved in NASH pathogenesis, including lipid metabolism, glucose homeostasis, and inflammation. In the phase 3 MAESTRO-NASH trial, resmetirom significantly improved NASH resolution, fibrosis, and LDL cholesterol levels compared to placebo, with a favorable safety profile. The tissue-specific action of resmetirom may also contribute to its efficacy and safety. The approval of resmetirom has opened new avenues for NASH drug development, emphasizing the importance of exploring novel mechanisms of action, developing targeted therapies, and embracing a more comprehensive approach to treatment. As the global burden of NASH continues to grow, the lessons learned from the success of resmetirom should inform future drug development strategies, offering hope to the millions of patients affected by this disease worldwide.