Cytokines hold huge potential for the treatment of disease due to their often fundamental roles in development and homeostasis. However, it is this same primary biological function that can both cause disease through dysregulation as well as prevent their therapeutic use due to systemic consequences arising from this inherent pleiotropy. Molecularly, this can be explained through an understanding of the receptor system specific to each cytokine and the cells on which they are expressed. This knowledge has been exploited to yield muteins (mutated proteins) that exhibit selective, and sometimes novel, biological properties dependent upon receptor subunit usage. In some cases, these muteins have been evaluated in clinical trials and have been approved for clinical use; in most instances, however, these muteins are not suitable for therapeutic application due to intrinsic characteristics of the muteins themselves or the cellular and receptor system to which they are directed. Ultimately, molecular insight to the biological processes governing disease pathology underlies the successful application of mutein-based therapy. The clinical success enjoyed by a subset of these proteins signals the advent of a new mode of therapeutic protein development.