The prevalence of non-alcoholic steatohepatitis (NASH) is increasing worldwide, yet there are no effective treatments. A decade has passed since initial lipidomic analyses of liver tissues from patients with non-alcoholic fatty liver disease. We have learned that liver cells from patients with NASH have an abnormal lipid composition, and the accumulation of lipids leads to organelle dysfunction, cell injury and death, and chronic inflammation, called liptoxicity. We review the lipid species and metabolic pathways that contribute to pathogenesis of NASH, as well as potential therapeutic targets, including enzymes involved in fatty acid and triglyceride synthesis, bioactive sphingolipids and polyunsaturated-derived eicosanoids and specialized proresolving lipid mediators.