Although the role of Hox genes in patterning the mammalian body plan has been studied extensively during embryonic and fetal development, relatively little is known concerning Hox gene function in adult animals. Analysis of mice with mutant Hoxa9, Hoxb9, and Hoxd9 genes shows that these paralogous genes are required for mediating the expansion and/or differentiation of the mammary epithelium ductal system in response to pregnancy. Mothers with these three mutant genes cannot raise their own pups, but the pups can be rescued by fostering by wild-type mothers. Histologically, the mammary glands of the mutant mothers seem normal before pregnancy but do not develop properly in response to pregnancy and parturition. Hoxa9, Hoxb9, and Hoxd9 are expressed normally in adult mammary glands, suggesting a direct role for these genes in the development of mammary tissue after pregnancy. Because loss-of-function mutations in these Hox genes cause hypoplasia of the mammary gland after pregnancy, it may be productive to look for misexpression of these genes in mammary carcinomas.