The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly understood and the mechanisms are still being elucidated. Mitochondrial dysfunction participates at different levels in NASH pathogenesis since it impairs fatty liver homeostasis and induces overproduction of free radicals that in turn trigger lipid peroxidation and cell death. In this article, we review the role of mitochondria in fat metabolism, energy homeostasis and reactive oxygen species production, with a focus on the role of mitochondrial impairment and uncoupling proteins in the pathophysiology of NASH progression. The potential effects of some molecules targeted to mitochondria are also discussed.