Cytokines represent one of the most versatile classes of biological molecules, and have served as remarkable models for understanding protein folding, recognition and signal transduction. They critically mediate cell-to-cell communication in development and immunity by engaging specific cell surface receptors, and in spite of their diverse repertoire of protein architectures, have largely converged on similar modes of interaction. While hotly pursued in the clinic as biomarkers and therapeutic targets in disease, cytokines remain a fascinating design challenge for protein engineers. I will talk about insights drawn from work at both ends of this spectrum, with a range of cytokine/receptor systems, including a fascinating new pairing that sheds new light on the evolution of two distinct types of cytokine and receptor families.