We have examined relationships among the adult beta-globin genes and pseudogenes of human, rabbit, goat, and mouse. This was done by looking at homology in noncoding and flanking regions which have not been as heavily affected by gene conversion as have the coding regions of these genes. The 3' half of the beta-globin clusters of human, rabbit, and goat all originated from a two-gene ancestral cluster. We refer to the two genes as proto-delta and proto-beta after their descendants in the human genome. We propose that the 3' half of the mouse cluster originated from a four-gene ancestral cluster consisting of a proto-delta, a proto-beta, a second proto-delta, and a second proto-beta. The delta-beta intergene distance is similar among these mammals, except where altered by a 5-kilobase insertion sequence in the goat. The nature of major length differences in the large intervening sequence was also examined. In descendants of proto-beta, this region has tended to increase in length by the insertion of sequence elements about 250 base pairs long. In contrast, major length changes in the large intervening sequence of descendants of proto-delta have been mediated by expansion or contraction of a short repetitive sequence, presumably involving unequal crossovers. Possible explanations for this asymmetry in behavior are explored.