Skin diseases manifesting classic sex-linked recessive patterns of inheritance provide straightforward problems in the mapping of disease loci. In contrast to autosomal disorders, in which the abnormal gene might be found on any chromosome, sex-linked diseases are found only on the human X chromosome. Thus, with a reasonable number of polymorphic DNA probes and families with living affected and unaffected males, disease loci can be easily mapped to the relevant subregions of the X chromosome. The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by eczema, immunodeficiency, and thrombocytopenia. Boys with WAS suffer from skin diseases, bleeding problems, recurrent infections, and lymphoid malignancies. In contrast, females who carry the WAS gene are entirely normal, as the abnormal X chromosome is selectively inactivated in cells of hematopoietic origin. Using restriction fragment length polymorphisms (RFLPs) and appropriate families, the WAS locus has been mapped to the proximal portion of the short arm of the X chromosome (Xp11). Prenatal diagnosis is now possible using specific RFLP markers. Moreover, combining RFLP studies with methylation analysis has allowed identification of all female carriers. Although the abnormal gene and protein that are responsible for WAS are currently unknown, studies using yeast artificial chromosomes containing portions of human Xp11 should ultimately allow for the cloning and characterization of the WAS gene. As this gene is expressed primarily in cells of bone marrow origin, WAS is an excellent candidate disease for gene therapy.