The association between the pathogenesis and natural course of nonalcoholic fatty liver disease (NAFLD) and skeletal muscle dysfunction is increasingly recognized. These obesity-associated disorders originate primarily from sustained caloric excess, gradually disrupting cellular and molecular mechanisms of the adipose-muscle-liver axis resulting in end-stage tissue injury exemplified by cirrhosis and sarcopenia. These major clinical phenotypes develop through complex organ-tissue interactions from the earliest stages of NAFLD. While the role of adipose tissue expansion and remodeling is well established in the development of NAFLD, less is known about the specific interplay between skeletal muscle and the liver in this process. Here, the relation-ship between skeletal muscle and liver in various stages of NAFLD progression is reviewed. Current knowledge of the pathophysi-ology is summarized with the goal of better understanding the natural history, risk stratification, and management of NAFLD.