Elevated plasma triglyceride (TG) concentrations are associated with an increased risk of atherosclerotic cardiovascular disease (CVD), hepatic steatosis and pancreatitis. Existing pharmacotherapies, such as fibrates, n-3 polyunsaturated fatty acids (PUFAs) and niacin, are partially efficacious in correcting elevated plasma TG. However, several new TG-lowering agents are in development that can regulate the transport of triglyceride-rich lipoproteins (TRLs) by modulating key enzymes, receptors or ligands involved in their metabolism. Balanced dual peroxisome proliferator-activated receptor (PPAR) α/γ agonists, inhibitors of microsomal triglyceride transfer protein (MTTP) and acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1), incretin mimetics, and apolipoprotein (apo) B-targeted antisense oligonucleotides (ASOs) can all decrease the production and secretion of TRLs; inhibitors of cholesteryl ester transfer protein (CETP) and angiopoietin-like proteins (ANGPTLs) 3 and 4, monoclonal antibodies (Mabs) against proprotein convertase subtilisin/kexin type 9 (PCSK9), apoC-III-targeted ASOs, selective peroxisome proliferator-activated receptor modulators (SPPARMs), and lipoprotein lipase (LPL) gene replacement therapy (alipogene tiparvovec) enhance the catabolism and clearance of TRLs; dual PPAR-α/δ agonists and n-3 polyunsaturated fatty acids can lower plasma TG by regulating both TRL secretion and catabolism. Varying degrees of TG reduction have been reported with the use of these therapies, and for some agents such as CETP inhibitors and PCSK9 Mabs findings have not been consistent. Whether they reduce CVD events has not been established. Trials investigating the effect of CETP inhibitors (anacetrapib and evacetrapib) and PCSK9 Mabs (AMG-145 and REGN727/SAR236553) on CVD outcomes are currently in progress, although these agents also regulate LDL metabolism and, in the case of CETP inhibitors, HDL metabolism. Further to CVD risk reduction, these new treatments might also have a potential role in the management of diabetes and non-alcoholic fatty liver disease owing to their insulin-sensitizing action (PPAR-α/γ agonists) and potential capacity to decrease hepatic TG accumulation (PPAR-α/δ agonists and DGAT-1 inhibitors), but this needs to be tested in future trials. We summarize the clinical trial findings regarding the efficacy and safety of these novel therapies for hypertriglyceridemia. © 2014 Elsevier B.V. All rights reserved.