Cytokines are secreted or membrane-presented molecules that mediate broad cellular functions, including development, differentiation, growth and survival. Accordingly, the regulation of cytokine activity is extraordinarily important both physiologically and pathologically. Cytokine and/or cytokine receptor engineering is being widely investigated to safely and effectively modulate cytokine activity for therapeutic benefit. IL-2 in particular has been extensively engineered, to create IL-2 variants that differentially exhibit activities on regulatory T cells to potentially treat autoimmune disease versus effector T cells to augment antitumour effects. Additionally, engineering approaches are being applied to many other cytokines such as IL-10, interferons and IL-1 family cytokines, given their immunosuppressive and/or antiviral and anticancer effects. In modulating the actions of cytokines, the strategies used have been broad, including altering affinities of cytokines for their receptors, prolonging cytokine half-lives in vivo and fine-tuning cytokine actions. The field is rapidly expanding, with extensive efforts to create improved therapeutics for a range of diseases.