The TNF family ligand ectodysplasin A (EDA) and its receptor EDAR are required for proper development of skin appendages such as hair, teeth and eccrine sweat glands. Loss of function mutations in the Eda gene cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition that can be ameliorated in mice and dogs by timely administration of recombinant EDA. The Eda gene on the X chromosome is transcribed as multiple splice variants, only two of which code for the receptor-binding C-terminal TNF homology domain. These two variants code for 391- and 389-amino acid-long proteins called EDA1 and EDA2. EDA1 binds EDAR, whereas EDA2 binds to another receptor, XEDAR. The biology of EDA2 and XEDAR is distinct from that of EDA1. Indeed, XEDAR-deficient mice have no obvious ectodermal dysplasia phenotype, whereas mice deficient in EDA, EDAR, or the signaling adaptor protein EDARADD all display virtually indistinguishable ectodermal dysplasia phenotypes, indicating the predominance of the EDA1-EDAR axis in the development of skin-derived appendages.