The increasing prevalence of overnutrition and reduced activity has led to a worldwide epidemic of obesity. In many cases, this is associated with insulin resistance, an inability of the hormone to direct its physiological actions appropriately. A number of disease states accompany insulin resistance such as type 2 diabetes mellitus, the metabolic syndrome, and non-alcoholic fatty liver disease. Though the pathways by which insulin controls hepatic glucose output have been of intense study in recent years, considerably less attention has been devoted to how lipid metabolism is regulated. Thus, both the proximal signaling pathways as well as the more distal targets of insulin remain uncertain. In this review, we consider the signaling pathways by which insulin controls the synthesis and accumulation of lipids in the mammalian liver and, in particular, how this might lead to abnormal triglyceride deposition in liver during insulin-resistant states.