Regulation of the immune response by members of the immunoregulatory signaling family of molecules is achieved by positive and negative signals delivered through immunotyrosine based inhibitory and activatory motifs. This results in a regulation of phosphorylation by tyrosine kinases and phosphatases. Many members of this family are found in the leucocyte receptor complex on human chromosome 19q13.4: the location for the genes for the KIR molecules, the ILT/LIR molecules, the NKp46, FcαR and LAIR. Many of these molecules are expressed by NK cells or by myeloid cells. They all have functional activities, which enable them to either trigger or inhibit immune effector functions. A number of them are receptors, which recognize MHC Class I molecules and are responsible for preventing NK cytolysis of normal cells. The genes for several other molecules, which also have the ability to regulate the immune response through either triggering or inhibitory signals have also been mapped to chromosomes other than 19q13.4. The emerging CMRF-35 family of molecules is related but the genes for these molecules map to a complex on human chromosome 17q22-24. This complex includes the two members, CMRF-35A and CMRF-35H that have been described to date. These molecules are expressed widely throughout the haematopoietic lineage and have the ability to trigger and inhibit immune cell functions. This review discusses these molecules and what is known about their regulatory functions.