The underlying causes of nonalcoholic fatty liver disease are unclear, although recent evidence has implicated the endoplasmic reticulum in both the development of steatosis and progression to nonalcoholic steatohepatitis. Disruption of endoplasmic reticulum homeostasis, often termed ER stress, has been observed in liver and adipose tissue of humans with nonalcoholic fatty liver disease and/or obesity. Importantly, the signaling pathway activated by disruption of endoplasmic reticulum homeostasis, the unfolded protein response, has been linked to lipid and membrane biosynthesis, insulin action, inflammation, and apoptosis. Therefore, understanding the mechanisms that disrupt endoplasmic reticulum homeostasis in nonalcoholic fatty liver disease and the role of the unfolded protein response in the broader context of chronic, metabolic diseases have become topics of intense investigation. The present review examines the endoplasmic reticulum and the unfolded protein response in the context of nonalcoholic fatty liver disease.