Interleukin-3 (IL-3) is a pleiotropic cytokine involved in the regulation of the proliferation, differentiation, survival and function of normal and malignant hematopoietic cells. The receptor for IL-3 is expressed at relatively small levels in all these cells, except for stem/progenitor cells in acute myeloid leukaemia and in chronic myeloid leukaemia cells where it is expressed at relatively high levels. This relatively high expression of the IL-3 α receptor (IL3Rα) on leukaemic stem /progenitor cells correlates clinically with unfavourable prognosis and reduced patient survival, and has spurred interest in developing new therapeutic monoclonal antibodies such as 7G3/CSL362 and drug conjugates that selectively target the stem/progenitor cell compartment Recently, a high affinity receptor binding variant of IL-3 fused to diphtheria toxin was shown to kill malignant progenitors in AML patients whilst sparing normal progenitors. How the replacement of a single amino acid, K116W, converts IL-3 into a ‘superkine’ with up to a hundredfold increase in receptor binding and tenfold increase in biological activity is a puzzle. Here we have determined the crystal structures of the IL-3 superkine bound to IL3Rα as well as the corresponding wild-type complex. A surprising feature of the structures is that the receptor engages both the WT and superkine IL-3 in a very different way to closely related members of the Type I cytokine receptor superfamily. The crystallographic studies coupled with molecular dynamics simulations and functional studies provide the molecular basis for the enhanced binding affinity of the superkine for its receptor.