Crystal structure analysis of α-helical cytokine-receptor complexes has provided numerous insights into the molecular recognition events that initiate essential cellular responses. Three-dimensional structure information gleaned from crystallographic studies has been used to understand the signal transduction process and is now guiding the design of clinically useful cytokine agonists and antagonists. The structures of twelve cytokines bound to their soluble receptor fragments have been determined to date. Stunning improvements in molecular biology as well as in crystallographic methods and equipment have greatly reduced the time required for structure determination, allowing one to focus on validating structure-based hypotheses. Examples that demonstrate the impact of this approach are described here as well as a general overview of cytokine-receptor structural biology. Despite success in defining extracellular cytokine-receptor molecular recognition events, elucidation of the intracellular receptor and associated kinase domains remains a formidable challenge.