The class II α-helical cytokine family consists of eleven members including the interferons, interleukin-10 (IL-10) and several newly discovered IL-10 homologs. The molecules display a vast array of biologic activities including the ability to induce an antiviral state, modulate inflammatory responses, and inhibit cell growth. Biologic activity is dependent on cytokine-dependent aggregation of two different cell-surface receptors. The detailed protein-protein interactions that initiate these biologic responses are amenable to study using X-ray crystallographic methods. In this article, I summarize my laboratory's contributions to understanding these recognition processes using IL-10 as the prototypic class II cytokine.