Abstract: Since its elucidation as the first cytokine/receptor complex structure nearly twenty years ago, the growth hormone paradigm has remained a remarkably good guide to understanding the molecular recognition, assembly and signaling principles of most cytokine receptor systems, whether or not they fell within the expansive superfamily of hemopoietic cytokines. These latter soluble proteins''variously called lymphokines, interleukins, colony stimulating factors, growth hormones and interferons''control the pace of growth and course of progressive differentiation in blood cell types, as well as trigger immune defense programs in the body. Sharing little to no sequence similarity, these proteins nevertheless adopt a unique helical fold that dictates their common interactions with an expansive family of membrane-spanning receptors, that likewise share an ancestral link. I will discuss two recent molecular complexes in this field that illustrate how our core concepts of these conserved protein architectures and their specific engagements have evolved over time as we run into some intriguing divergences. The first case is the solution of the first activated ligand/receptor complex for an IL-1 family cytokine (the first interleukin, which is actually not a helical factor) that poses an interesting test of the growth hormone model, and for which we can now trace a divergent evolutionary path from another cytokine family. The second receptor complex is that of one of the most recently discovered hemopoietic cytokines that is now revealed as a helical factor that binds to a receptor family outside of the clan, in competition with a renegade class of membrane-tethered helical cytokines. REFERENCES: Thomas, C, Bazan, JF, Garcia, KC (2012) Structure of the activating IL-1 receptor signaling complex. Nature Struct. Molec. Biol., published online 18 March; doi:10.1038/nsmb.2260 Lingel, A, Weiss, TM, Nieebuhr, M, Pan, B, Appleton, B, Wiesmann, C, Bazan, JF, Fairbrother, WJ (2009) Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors''insight into heterotrimeric IL-1 signaling complexes. Structure 17, 1398-1410. Bazan, JF, de Sauvage, FJ (2009) Structural ties between cholesterol transport and morphogen signaling. Cell 138, 1055-1056.