Soluble cytokine receptors naturally arise from genes encoding membrane-bound receptors or are direct derivatives of the receptors themselves. There is mounting evidence that soluble receptors play important roles in human disease states. In many cases, soluble receptors appear to play an integral part in the dynamic interaction between ligands and their membrane-bound receptors in maintaining and restoring health after a pathological insult but, in some instances, dysregulated expression of soluble receptors can contribute to disease pathology. Nonetheless, an appreciation of the biological actions of soluble receptors, particularly as cytokine inhibitors, has led to their therapeutic use in human diseases. Although early clinical trials of soluble receptors have had unexpected toxicities, their application in medicine continues to advance and it is likely that soluble receptors will join hormones, cytokines, and growth factors as established biological therapies. J. Leukoc. Biol. 64: 135–146; 1998.