Alternative RNA splicing is a process by which introns are removed and exons are assembled to construct different RNA transcript isoforms from a single pre-mRNA. Previous studies have demonstrated an association between dysregulation of RNA splicing and a number of clinical syndromes, but the generality to common disease has not been established. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease affecting one-third of adults worldwide, increasing the risk of cirrhosis and hepatocellular carcinoma (HCC). In this review we focus on the change in alternative RNA splicing in fatty liver disease and the role for splicing regulation in disease progression.