Severe combined immunodeficiency disease (SCID) refers to a spectrum of inherited immunodeficiencies that together represent the most severe forms of primary immunodeficiency in humans. Recent work has shown that many of these diseases, as well as other forms of immunodeficiency, result from defects in cytokine signalling pathways. Such defects can prevent normal development of lymphoid lineages and/or compromise cytokine signalling by these cells. These natural 'experiments' in human genetics have shown the non-redundant role for several cytokines or cytokine signalling molecules. Moreover, a comparison of the phenotypes of humans with SCID to analogous mouse-knockout models has shown not only expected similarities, but also unexpected differences in cytokine signalling between humans and mice.