The growth hormone receptor (GHR) has been the archetype for the class I cytokine receptor family. The original paradigm for how growth hormone (GH) binding to the GHR led to activation of the associated JAK2 was based on biophysical and structural studies over 20 years ago which showed that growth hormone binding to the extracellular domain of the receptor occurred in a sequential fashion, first binding to a high affinity site on a single receptor (site 1) and then binding to a lower affinity site (site 2) on a second receptor. We have recently defined a new paradigm by demonstrating a complete mechanistic model for JAK2 activation by the pre-dimerized GHR. We utilised multiple approaches to define this model including FRET to monitor positioning of the JAK2 binding motif, leucine-zipper receptor constructs to control receptor transmembrane (TM) helix position, atomistic modelling of TM helix interactions and docking of JAK2 kinase and inhibitory pseudokinase crystal structures with an opposing pair in trans (1). Surprisingly, we identified that receptor activation induces a separation of its JAK2 binding motifs which leads to removal of the pseudokinase domain from the kinase domain of the partner JAK2 and pairing of the two kinase domains, facilitating trans-activation. This model may represent a common mechanism to other class I cytokine receptors.