Adiponectin is an abundantly expressed adipokine in adipose tissue and has direct insulin sensitizing activity. We have proposed the following adiponectin hypothesis. Interactions of genetic factors such as single nucleotide polymorphisms (SNPs) in the Adiponectin gene and environmental factors causing obesity result in hypoadiponectinaemia, which appears to play an important causal role in obesity-linked insulin resistance, type 2 diabetes and the metabolic syndrome. We have cloned the adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin. AdipoR1 and AdipoR2 are down-regulated in obesity-linked insulin resistance. Up-regulation of adiponectin or adiponectin receptors may represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance.