The IL-3 receptor signalling complex is a regulator of normal and malignant hemopoiesis and has also been implicated in several pathological activities outside of hemopoiesis. In hemopoietic cells IL-3 induces dimerisation of its receptor IL-3R and βc subunits and the formation of a high order complex, the structure of which we have recently solved. However, how the IL-3 receptor signals as it undergoes oligomerisation is poorly understood, as is the quality of the signalling and how it differs from the related GM-CSF receptor. Our laboratory is utilizing novel purification strategies using StrepTag and unique antibodies that have identified a distinct set of proteins and distinct interactions involved in IL-3 signalling. Proteomic analysis followed by validation experiments allowed us to: 1) revisit the role of JAK1 and JAK2 in IL-3-initiated signalling, which suggests distinct roles depending on hexameric or dodecameric receptor assembly; 2) identify a precise mechanism of SHP2 activation in response to IL-3 which involves not only JAK kinases but also IL-3Rα-associated Lyn kinase; 3) identify distinct docking sites in βc responsible for the interaction of SHP2 with the IL-3 receptor in vivo. This distinct JAK/SHP2/Lyn signalling pathway downstream of the IL-3 receptor complex may have important implications for certain types of leukaemia.