Despite our tendency to overeat, excessive fat accumulation was prevented in the past, as any excess weight soon impaired the physical fitness required to gather food, and to either fight or escape predators or foes. However, for the first time in human history, a large fraction of the population in affluent countries can now concomitantly indulge in rich food and physical idleness. The imbalance between food intake and the limited amount of fuels that can be burnt by mitochondria in inactive persons causes obesity, whose prevalence is increasing in affluent countries [1]. Obesity can lead to insulin resistance and hepatic steatosis, which triggers apoptosis, necrosis, Mallory bodies, an inflammatory cell infiltrate, and fibrosis in some patients [2]. The association of steatosis with these other liver lesions is called steatohepatitis, and the term non-alcoholic steatohepatitis (NASH) mostly refers to the steatohepatitis associated with insulin resistance. Although the successive events triggering NASH are not fully understood, it seems that fat accumulation in myocytes triggers insulin resistance in muscle, thus causing pancreatic b-cells to release large amounts of insulin. High insulin levels increase hepatic free fatty acid (FFA) synthesis in the liver to cause steatosis, which can trigger NASH in some patients. The purpose of this review is to discuss the evidence, mechanisms and implications of mitochondrial dysfunction at the successive steps leading to NASH, as already partially reviewed elsewhere [3–8]. Beforehand, however, it may be useful to briefly recall some salient features of mitochondria.