Maintenance of the haematopoietic and immune systems is largely controlled by the secretion of cytokines. Cytokine exposure initiates an intracellular signalling cascade that is driven by activation of a family of receptor-bound tyrosine kinases known as the JAKs (Janus Kinases). Under physiological conditions, JAK activation and signalling is tightly regulated, in particular by the SOCS (Suppressors of Cytokine Signalling) family of proteins. However, in many disease situations, mutant JAK overcomes its regulation by SOCS, leading to haematological malignancies. Using structural and biochemical techniques, we have determined the molecular basis for the mechanism of action of SOCS3. Our data indicates that SOCS3 binds to an evolutionarily conserved sequence motif unique to JAK1, JAK2, and TYK2, but absent in JAK3. SOCS3 then directly inhibits the catalytic domains of those three kinases via a mechanism that is non-competitive towards ATP. Surprisingly, we found that SOCS3 binds simultaneously to the JAK and its associated cytokine receptor; revealing how SOCS specificity is generated and explaining why SOCS3 inhibits only a subset of cytokines. Recently, these results have been supported by our X-ray crystal structure of a SOCS3/JAK2/gp130 protein complex, which has revealed the SOCS/JAK interaction surface and detailed the molecular mechanism of SOCS action. These data have allowed us to develop a model which explains the inhibition of JAK by SOCS3 and SOCS1.