The olfactory receptor (OR) gene superfamily is the largest in the mammalian genome. Human OR genes appear in clusters with 10 or more members located on almost all human chromosomes and with some chromosomes containing more than one cluster. We demonstrated that unequal crossovers between OR clusters are responsible for the formation of chromosome rearrangements. Several studies demonstrated that repeated sequences, located on the same chromosome at a distance of few megabases, predispose to homologous unequal recombination leading to chromosome microrearrangements. Deletions and reciprocal duplications can be mediated by duplicons having the same orientation whereas inversions seem to be due to unequal crossovers between duplicons with an inverted orientation.It seems likely that some macrorearrangements may also be mediated by the same mechanisms.Repeated sequences located on the same chromosome could be responsible for pericentric or paracentric inversions (according to their location on different chromosome arms or on the same arm) or for more complex rearrangements depending on the number of crossovers occurring between the two duplicons. Repeats located on different chromosomes could be responsible for translocations. Thus OR gene clusters might be the substrate for the formation of both intra- and interchromosomal rearrangements.We found that the common chromosome rearrangement inv dup(8p) (inverted duplication of 8p; estimated frequency 1:10-15000), associated with a severe malformation phenotype, is mediated by two closely spaced 8p-OR repeats. We also found that mothers of inv dup(8p) patients are all heterozygous for a benign inversion polymorphism involving the 8p-OR region.Thus this polymorphism seems to produce increased susceptibility to unequal recombination leading to the formation of a chromosome rearrangement.We also demonstrated that the deletion 8p22-p23.1, of whom several cases with similar cytogenetics breakpoints have been reported, is also mediated by the 8p-OR clusters.