Obesity has now reached pandemic levels, with a quarter of the world’s population being overweight or obese and thus at a greater risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD) [1•]. Largescale biobanks, combined with genome-wide discovery efforts, have identified thousands of loci associated with obesity traits including body composition, fat distribution and their causal relationships with disease risk. These findings have begun to shed light on some of the biological mechanisms driving human adiposity. In conjunction with comprehensive functional annotation efforts, such as cell-level transcriptome maps and phenotypic analyses of model organisms, we are poised to reveal fundamental biology and disease risk mechanisms at an unparalleled resolution. Integration of genetic and experimental approaches will be pivotal in the translation of genomic signals into the causal and functional mechanisms behind obesity, with the potential of delivering precision medicine strategies in the near future.