Homologous paired receptors are located in the same gene cluster and are thought to have evolved through gene duplication. Sequence features such as the presence of an ITIM-like sequence in the 3' untranslated region of some activating receptors imply that the activating members of the pair likely evolved from the inhibitory members. A number of pathogens interact with the inhibitory member of a pair as a means of immune evasion or viral entry, suggesting that activating members with similar binding competencies may be an evolutionary response to this mechanism.  This hypothesis is known as the "counterbalance theory" and these evolutionary dynamics represent an evolutionary arms race between pathogens and the host immune system. The evolutionary pressures on some paired-receptor families have been described as examples of the "Red Queen" effect.
Including non-paired examples, over 300 potential immune inhibitory receptors have been identified in the human genome. There are strong indications that paired receptors are rapidly and recently evolving. These genetic regions have high levels of gene polymorphism, and the gene repertoires found in the genomes of closely related lineages vary significantly. The selective pressure experienced by the host from pathogens is thought to underlie this rapid evolution.
Although paired receptors are best characterized as part of the human and mouse immune systems, they have also been studied in other organisms. The chicken (Gallus gallus domesticus) genome contains a number of examples including a very large family, the chicken Ig-like receptors (CHIR) with over 100 members. Paired receptor evolution has also been studied in Xenopus (clawed frog) species. The adaptive immune system is unique to jawed vertebrates, but an example of a paired receptor family has been identified in a jawless vertebrate, termed agnathan paired receptors resembling Ag receptors (APAR) in the hagfish.