Nonalcoholic fatty liver disease represents a wide spectrum of conditions and is currently the most common form of chronic liver disease affecting both adults and children in the United States and many other parts of the world. Great effort has been focused on the development of novel therapies for those patients with the more advanced forms of the disease, in particular those with nonalcoholic steatohepatitis (NASH) and liver fibrosis that can be associated with significant morbidity and mortality. In this review, the authors focus on the role of cell death and sterile inflammatory pathways as well as the self-perpetuating deleterious cycle they may trigger as novel therapeutic targets for the treatment of fibrotic NASH.