This review discusses the challenges in NASH clinical trials, emphasizing the need for a more holistic approach. NASH, now termed MASH, is a systemic metabolic disorder with both hepatic and extrahepatic consequences. Lifestyle changes are the cornerstone of NASH treatment, as many trials have failed to identify effective pharmacological treatments. The review highlights the high heterogeneity of NASH, influenced by genetic factors, insulin resistance, lipotoxicity, oxidative stress, and hypoxia, leading to chronic inflammation and fibrosis. The failure of NASH trials is attributed to the complexity of the disease, requiring personalized medicine approaches with noninvasive biomarkers. Future trials should focus on systemic determinants, including cardiovascular, kidney, and metabolic outcomes, rather than relying solely on liver histology. The review also discusses the limitations of liver biopsy and noninvasive tests, which are not always reliable. Placebo responses vary widely, complicating trial outcomes. The failure of NASH trials is attributed to factors such as patient heterogeneity, slow disease progression, and the need for liver biopsies. The review concludes that NASH is a multisystem disease, and future trials should consider cardiovascular and metabolic outcomes to better address its systemic nature.This review discusses the challenges in NASH clinical trials, emphasizing the need for a more holistic approach. NASH, now termed MASH, is a systemic metabolic disorder with both hepatic and extrahepatic consequences. Lifestyle changes are the cornerstone of NASH treatment, as many trials have failed to identify effective pharmacological treatments. The review highlights the high heterogeneity of NASH, influenced by genetic factors, insulin resistance, lipotoxicity, oxidative stress, and hypoxia, leading to chronic inflammation and fibrosis. The failure of NASH trials is attributed to the complexity of the disease, requiring personalized medicine approaches with noninvasive biomarkers. Future trials should focus on systemic determinants, including cardiovascular, kidney, and metabolic outcomes, rather than relying solely on liver histology. The review also discusses the limitations of liver biopsy and noninvasive tests, which are not always reliable. Placebo responses vary widely, complicating trial outcomes. The failure of NASH trials is attributed to factors such as patient heterogeneity, slow disease progression, and the need for liver biopsies. The review concludes that NASH is a multisystem disease, and future trials should consider cardiovascular and metabolic outcomes to better address its systemic nature.