Members of the SOCS (suppressor of cytokine signalling) family of proteins play key roles in the negative regulation of cytokine signal transduction. A series of elegant biochemical and molecular biological studies has revealed that these proteins act in a negative feedback loop, inhibiting the cytokine-activated Janus kinase/signal transducers and activators of transcription (JAK/ STAT) signalling pathway to modulate cellular responses. Although structurally related, the precise mechanisms of SOCS-1, SOCS-3 and cytokine-inducible SH2-containing protein (CIS) action vary. Direct interaction of SOCS SH2 domains with the JAK kinases or cytokine receptors allows their recruitment to the signalling complex, where they inhibit JAK catalytic activity or block access of the STATs to receptor binding sites. The defining feature of the family, the C-terminal SOCS box domain, appears dispensable for these actions but is likely to play a key role in negative regulation of signalling by targeting molecules associated with the SOCS proteins for degradation. The relevance of SOCS-mediated regulation of cytokine responses has been brought into sharp focus by the dramatic phenotypes of mice lacking these regulators. Indispensable roles for members of this family have been identified in the regulation of interferon γ, growth hormone and erythropoietin, and the absence of SOCS-1 or SOCS-3 is lethal in mice.