This article focuses on the assembly mechanisms used by α-helical cytokine-receptor signaling complexes to activate the JAK/STAT signaling pathway. Structural features of α-helical cytokines and their cognate cell surface receptors are reviewed. This is followed by an analysis of common and distinct molecular recognition strategies used by different classes of α-helical cytokines to initiate cell signaling. These studies show that cytokines and receptors encode distinct binding chemistries into their amino acid sequences, which are displayed on a limited number of common structural scaffolds. These structural features control cytokine-receptor binding affinity, specificity, and also regulate the assembly of several structurally distinct cytokine-receptor complexes that are essential for cellular responses.