The prevalence of hypertriglyceridemia (HTG) has increased multifold over the past several decades mostly due to the rising prevalence of obesity, metabolic syndrome, and diabetes mellitus (DM). One of the most untoward complications of severe HTG is acute pancreatitis (AP) requiring hospitalization for intensive treatment. The risk for AP is more clearly defined at triglyceride levels >1000 mg/dL. The prevention of HTG-associated AP requires a multifaceted approach with initiation of weight loss strategies, limitation of fat and simple carbohydrates from diet, restriction of alcohol, control of secondary risk factors such as uncontrolled diabetes, discontinuation of offending medications when possible, and initiation of lipid-lowering medications. Pharmacologic options for very high TG include fibrates, niacin, and omega-3 polyunsaturated fatty acids (OM3FA), composed primarily of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Newer and emerging classes of medications include inhibitors of APOC3 (apolipoprotein C3) and ANGPTL (angiopoietin-like protein) to reduce circulating triglycerides. In patients with uncontrolled hyperglycemia, insulin with or without heparin can be very effective in the acute inpatient setting. In some studies, plasmapheresis has also been shown to be an effective modality for urgent lowering of TG levels.