Chemokine and chemoattractant receptors are members of the large superfamily of G protein-coupled receptors (GPCR), which control leukocyte chemotaxis. In addition to their physiological role, several chemokine and chemoattractant receptors, such as CCR5 and Duffy, have been directly associated with pathogen entry. GPR33 is an orphan chemoattractant GPCR that was previously identified as a pseudogene in humans. GPR33 evolved in mammals about 125-190 million years ago. The cloning and analysis of more than 120 mammalian GPR33 orthologs from 16 of 18 eutherian orders revealed an inactivation of this chemoattractant GPCR not only in humans, but also in several great ape and rodent species. Intriguingly, in all ape and some rodent species where the inactivation occurred, samples harbored both pseudogene and intact gene variants. The analysis of over 1200 human individuals representing all major linguistic groups revealed that the intact allele of GPR33 is still present in the human population. Estimates of the age of the human alleles suggest inactivation in the past 1 million years. Similarly, analysis of more than 120 wild-caught gray rats (Rattus norvegicus), revealed that inactivation of gpr33 is worldwide fixed and occurred in less than 0.7 million years ago. The coincidental inactivation and its fixation in several species of distantly related mammalian orders suggest a selective pressure on this chemoattractant receptor gene.