Adiponectin, a protein exclusively secreted by adipose tissue but present at low levels in obesity, is now widely recognised as a key determinant of insulin sensitivity and of protection against obesity-associated metabolic syndrome. In this review we explain how genetic findings have contributed to a better understanding of the physiological role of adiponectin in humans. The adiponectin-encoding gene, ADIPOQ (ACDC), is very polymorphic: many frequent exonic synonymous, intronic and promoter single-nucleotide polymorphisms (SNPs) have been identified, as well as a few rare exonic amino acid substitutions. Several of these variations additively contribute to the modulation of adiponectin level and function, and associate with insulin sensitivity, type 2 diabetes and vascular complications of obesity.