Through the sequencing of more than 640,000 human exomes, researchers identify rare gene coding variants strongly associated with body mass index (BMI) - including the variant GPR75, which conferred protection from obesity in mouse models. Not only do the findings provide potential therapeutic targets for treating obesity, but they also demonstrate the power and versatility of massive-scale exome sequencing in discovering rare coding variants that could offer new and potentially translatable biological functions. Body fat is a highly heritable trait and the obesity to which body fat contributes is linked to a variety of human diseases, including diabetes, cancer, and heart disease. While it's known that genetic factors play an essential role in energy balance and body fat regulation, how genes and rare coding variants can predispose or protect individuals from obesity is not fully understood. Understanding this could provide a pathway to developing safe and effective therapeutic strategies for treating obesity. Parsa Akbari et al. sequenced the exomes of 645,626 individuals from the United Kingdom, United States and Mexico and discovered a set of 16 genes in which rare coding variants exhibited an exome-wide significant association with BMI. One of these, GPR75 - a brain-expressed G protein-coupled receptor - was observed in roughly 4 out of every 10,000 sequenced individuals and associated with lower BMI. Knock-out of this gene in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet. "The principles of discovery exemplified in the study of Akbari et al. go beyond that of body weight control and obesity," write Giles Yeo and Stephan O'Rahilly in a related Perspective. "It is likely that human exome sequencing at scale will become an increasingly important entry point for the discovery of mechanistic insights into mammalian biology."