Atomistic molecular dynamics simulations have been used to investigate the conformational changes within the extracellular domain (ECD) of the growth hormone receptor (GHR), the prolactin receptor (PRLR), erythropoietin receptor (EPOR) and the epidermal growth factor associated with the binding or removal of ligand shedding new light on the mechanism of activation of these receptors at an atomic level. In all cases, the removal of the cytokine from the ligand-bound homodimeric receptor complexes results in a rotation of the two subunits relative to each other of between 30° and 45°. The magnitude and direction of the motion observed in the simulations of GHR and EPOR are in close agreement with experiment. The similarity of the motions in all these cases and in multiple simulations suggests that the relative rotation of the ECDs could represent a general mechanism of activation of cytokine receptors.