With the prevalence of obesity increasing worldwide, nonalcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease. Despite this, knowledge about the molecular mechanisms involved in NAFLD progression is still limited. Recent findings have shown that endoplasmic reticulum (ER) stress links inflammation and hepatocyte death, inherent to the transition from simple steatosis to nonalcoholic steatohepatitis (NASH). Here, we emphasize the central role of the ER stress response and its crosstalk with the inflammasome. We hope to provide new insight on the identification of ER stress-dependent pathways that contribute substantially to chronic liver disease progression as important triggers of cell death and inflammation, and therefore may represent potential therapeutic strategies.