This narrative review summarizes the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD). It begins by discussing the epidemiology of NAFLD and its association with obesity and type 2 diabetes (T2DM). The review then delves into the challenges of conducting randomized-controlled trials (RCTs) for regulatory approval, including differences between the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA). It highlights issues such as liver biopsy limitations, high screening failure rates, and variable placebo response rates. The review also outlines strategies for potential drug treatments, focusing on repurposing drugs originally developed for T2DM and obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (GLP1-RA), multi-agonists, and sodium-glucose transporter 2 inhibitors (SGLT2-Is). Additionally, it discusses specific liver-targeting molecules like resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, which are currently in Phase 3 clinical trials. The review concludes by emphasizing the potential benefits of combination therapy in NAFLD/MASLD, suggesting that addressing underlying metabolic issues may be more effective in early stages of the disease, while liver-targeting treatments may be crucial for advanced cases.This narrative review summarizes the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD). It begins by discussing the epidemiology of NAFLD and its association with obesity and type 2 diabetes (T2DM). The review then delves into the challenges of conducting randomized-controlled trials (RCTs) for regulatory approval, including differences between the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA). It highlights issues such as liver biopsy limitations, high screening failure rates, and variable placebo response rates. The review also outlines strategies for potential drug treatments, focusing on repurposing drugs originally developed for T2DM and obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (GLP1-RA), multi-agonists, and sodium-glucose transporter 2 inhibitors (SGLT2-Is). Additionally, it discusses specific liver-targeting molecules like resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, which are currently in Phase 3 clinical trials. The review concludes by emphasizing the potential benefits of combination therapy in NAFLD/MASLD, suggesting that addressing underlying metabolic issues may be more effective in early stages of the disease, while liver-targeting treatments may be crucial for advanced cases.