We report a comprehensive comparative analysis of human and mouse olfactory receptor (OR) genes encoding OR37 subtypes to determine the repertoire, chromosomal organization, and relatedness of these genes. Two OR37 clusters were found in both mouse (chromosome 4) and human (chromosome 9); with five genes in cluster I and three (mouse) and seven genes (human) in cluster II. The pronounced diversity of noncoding sequence regions in both genomic loci indicates a long-term coexistence of the two clusters and the genes within the clusters. In contrast, the coding regions, particularly of genes in cluster I, showed remarkably high sequence identity, a feature quite unique for OR genes. The conservation of only the coding sequences indicates that OR37 may be under negative selection pressure and suggests that the OR37 receptor family may be tuned to recognize distinct sets of signaling molecules. A comparison of mouse and human OR37 gene clusters revealed that genes in cluster I are highly related within each species whereas genes in cluster II are highly related across species. These data reflect a unique and complex evolutionary history of the OR37 family.