Obesity, insulin resistance, and diabetes are strongly linked to the accumulation of excessive lipids in the liver parenchyma, a condition known as nonalcoholic fatty liver disease (NAFLD). Given its association with obesity and related metabolic diseases, it is not surprising that the prevalence of NAFLD has dramatically increased in the past few decades. NAFLD has become the most common liver disease in many areas of the world. The term, NAFLD, encompasses a spectrum of disorders that ranges from simple steatosis to steatosis with inflammatory lesions (nonalcoholic steatohepatitis [NASH]). Although simple steatosis might be relatively benign, epidemiologic studies have linked NASH to greatly increased risk of developing cirrhosis and hepatocellular carcinoma. Yet despite this, there are no approved treatments for the disease, and it remains a significant unmet medical need. This Perspective will review some of the relevant literature on the topic and examine approved and experimental NASH therapeutic concepts that target intermediary metabolism, insulin resistance, and diabetes to treat this emerging public health problem.