Why do human beings get insulin resistance and Type 2 diabetes (T2D)? We know a lot about the signaling and transcriptional networks that promote or oppose insulin action in cultured cells and in mouse models, but are these the most relevant pathways in humans? In order to answer this, we can turn to studies of human genetics. GWAS analysis of human T2D has now implicated over 240 loci with roughly 500 independent association signals. The vast majority of these signals are located in noncoding regions of the genome. In virtually all cases for which it has been scrutinized, the mechanism of action of noncoding variants is to alter transcription factor binding and thus expression of key target genes. In this light, diseases like T2D and IR can be thought of as ‘enhancer-opathies’. In collaboration with Linus Tsai (BIDMC), Melina Claussnitzer (Broad), and others, we are using high-throughput CRISPR-based screening techniques to identify genes and enhancers that contribute to insulin resistance in human adipocytes. We predict which variants are most likely to be causal in disease pathogenesis, and then validate these predictions using variant switching. We are also identifying the upstream transcription factors whose binding are compromised by the presence of the variant.