Since 2008, significant advances have been made in understanding the role of diacylglycerol acyl transferase-1 (DGAT1) in disease states such as diabetes and obesity. Gene deletion and overexpression studies have provided important new insights into the function of DGAT1, as have the first reports from preclinical models of small-molecule inhibitor effects, which are discussed in this review in relation to the phenotypes of DGAT knockout and overexpression models. The progress of medicinal chemistry efforts has resulted in a new generation of DGAT1 inhibitors that have progressed into clinical development, with the leading compound LCQ-908 (Novartis AG) now in phase II clinical trials. This exciting progress has led researchers to anticipate that an understanding of the human pharmacology of DGAT1 inhibitors, as well as their potential as therapeutic agents for the treatment of diabetes and obesity, will be achieved in the next few years.