NAFLD has evolved as a serious public health problem in the USA and around the world. In fact, NASH-the most serious form of NAFLD-is predicted to become the leading cause of liver transplantation in the USA by the year 2020. The pathogenesis of NAFLD and NASH, in particular the mechanisms responsible for liver injury and fibrosis, is the result of a complex interplay between host and environmental factors, and is at the centre of intense investigation. In this Review, we focus on recently uncovered aspects of the genetic, biochemical, immunological and molecular events that are responsible for the development and progression of this highly prevalent and potentially serious disease. These studies bring new insight into this complex disorder and have led to the development of novel therapeutic and diagnostic strategies that might enable a personalized approach in the management of this disease.