The ectodysplasin (EDA) pathway, which is active during the development of ectodermal organs, including teeth, hairs, feathers, and mammary glands, and which is crucial for fine-tuning the developmental network controlling the number, size, and density of these structures, was discovered by studying human patients affected by anhidrotic/hypohidrotic ectodermal dysplasia. It comprises three main gene products: EDA, a ligand that belongs to the tumor necrosis factor (TNF)-α family, EDAR, a receptor related to the TNFα receptors, and EDARADD, a specific adaptor. This core pathway relies on downstream NF-κB pathway activation to regulate target genes. The pathway has recently been found to be associated with specific adaptations in natural populations: the magnitude of armor plates in sticklebacks and the hair structure in Asian human populations. Thus, despite its role in human disease, the EDA pathway is a ‘hopeful pathway' that could allow adaptive changes in ectodermal appendages which, as specialized interfaces with the environment, are considered hot-spots of morphological evolution.