The GM-CSF, IL-3, and IL-5 receptors constitute the βc family, playing important roles in inflammation, autoimmunity, and cancer. Typical of heterodimeric type I cytokine receptors, signaling requires recruitment of the shared subunit to the initial cytokine:α subunit binary complex through an affinity conversion mechanism. This critical process is poorly understood due to the paucity of crystal structures of both binary and ternary receptor complexes for the same cytokine. We have now solved the structure of the binary GM-CSF:GMRα complex at 2.8-Å resolution and compared it with the structure of the ternary complex, revealing distinct conformational changes. Guided by these differences we performed mutational and functional studies that, importantly, show GMRα interactions playing a major role in receptor signaling while βc interactions control high-affinity binding. These results support the notion that conformational changes underlie the mechanism of GM-CSF receptor activation and also suggest how related type I cytokine receptors signal. Display omitted •Crystal structure of human GM-CSF receptor binary complex•Improved structure of human GM-CSF receptor ternary complex•Mutational and functional studies reveal major interactions for receptor activation•Observed conformational changes underlie mechanism of receptor signaling GM-CSF receptor signaling is triggered in response to invading pathogens, but excessive GM-CSF signaling can lead to leukemia and inflammatory diseases. Broughton et al. report on the structural basis for cytokine recognition by the receptor in the binary and ternary states that reveal conformational changes leading to receptor activation.