Dietary lipids are efficiently absorbed by the small intestine, incorporated into triglyceride-rich lipoproteins (chylomicrons), and transported in the circulation to various tissues. Intestinal lipid absorption and mobilization and chylomicron synthesis and secretion are highly regulated processes. Elevated chylomicron production rate contributes to the dyslipidemia seen in common metabolic disorders such as insulin-resistant states and type 2 diabetes and likely increases the risk for atherosclerosis seen in these conditions. An in-depth understanding of the regulation of chylomicron production may provide leads for the development of drugs that could be of therapeutic utility in the prevention of dyslipidemia and atherosclerosis. Chylomicron secretion is subject to regulation by various factors, including diet, body weight, genetic variants, hormones, nutraceuticals, medications, and emerging interventions such as bariatric surgical procedures. In this review we discuss the regulation of chylomicron production, mechanisms that underlie chylomicron dysregulation, and potential avenues for future research.