The topic covered in this review is the regulation of hepatic VLDL production by fatty acids, with emphasis on the role of plasma free fatty acids. Hepatic VLDL production is primarily substrate driven, the most important regulatory substrate being fatty acids. Fatty acids may be derived from at least four sources: (1) de-novo lipogenesis, (2) cytoplasmic triglyceride stores, (3) fatty acids derived from lipoproteins taken up directly by the liver, or (4) exogenous fatty acids (plasma free fatty acids). Although the total flux of fatty acids reaching hepatocytes plays an important regulatory role in VLDL synthesis, it is the nutritional and hormonal state of the organism that ultimately determines the rate of VLDL secretion. Nutritional and hormonal factors will determine whether intracellular fatty acids are channelled into oxidative, storage or secretory pathways. Conditions associated with both elevated free fatty acid flux to the liver and elevated de-novo lipogenesis, such as occurs in hyperinsulinemic insulin-resistant states, have hepatocytes primed to channel fatty acids into secretory pathways, with consequent high rates of VLDL secretion. Insulin-resistant states are associated not only with the release of larger quantities of free fatty acids from the increased mass of circulating lipoproteins, particularly in the postprandial state, but also with reduced free fatty acid uptake and esterification by peripheral tissues. Thus a vicious cycle is set up in insulin-resistant states involving free fatty acids and hypertriglyceridemia.