Cytokine receptors are members of a diverse family of proteins that serve the dual function of recognizing their cognate ligands among a plethora of other factors and of initiating a series of cellular signals that ultimately lead to multiple cellular functions. Although cytokine receptors are only activated by their specific cytokines, some functional overlap occurs as a result of receptor subunit promiscuity, kinase recruitment and the activation of coincident signalling pathways. Knock-out experiments are extremely useful in helping to elucidate functionally relevant interactions between cytokine receptor activation, signalling molecules and cellular function. Defects in cytokine receptors or activation, signalling molecules continue to be identified as the underlying cause of clinical conditions. We discuss newly recognized clinical syndromes and recent research into the molecular basis of cytokine receptor activation that provides new insights into the role of cytokine receptors in normal physiology and disease.