Monoacylglycerol transferase 2 (MGAT2) is a pivotal enzyme in the monoacylglycerol pathway for triacylglycerol synthesis. The pathway for triacylglycerol synthesis has provided several attractive targets for drug discovery in the treatment of metabolic diseases. Marketed drugs that inhibit enzymes in this pathway include orlistat (pancreatic lipase inhibitor), lomitapide (mitochondrial transfer protein inhibitor), and mipomersen (apolipoprotein B synthesis inhibitor), but poor gastrointestinal (GI) tolerability or safety considerations have limited their use and indications. In addition, several inhibitors of diacylglycerol transferase 1 (DGAT1) have advanced to the clinic but were withdrawn due to poor GI tolerability. This report first discusses the biological rationale in support of inhibition of MGAT2 as a therapeutic approach that may offer a distinct and superior efficacy versus GI tolerability profile and then reviews advances in the discovery of small molecule MGAT2 inhibitors for the treatment of metabolic diseases and nonalcoholic steatohepatitis (NASH).