Biological activity and clinical efficacy of a therapeutic protein are contingent upon the structural stability, bioavailability, and clearance rates of the protein. In this review, we examine the class of 4-helical bundle cytokines for common stability properties that may affect biological structure and efficacy. Three critical stability features that are hallmarks of this class of cytokines are the pH dependence of structural stability, the presence of folding intermediates, and the population of aggregation intermediates. We hypothesize that certain cytokines have increased stability in acid to enable receptor-mediated clearance, and that reengineering local endocytic trafficking can result in dramatic improvements in global serum half-life and therapeutic efficacy. The common feature of folding and aggregation intermediates has implications on kinetic folding pathways, membrane permeability, solubility, and precipitation properties that are critical for commercial production, formulation, and delivery. Understanding the structural stability properties of this class of cytokines may help elucidate new approaches to improving therapeutic efficacy.