The first successful application of positional cloning to a disorder of the skin involved the identification of steroid sulfatase as the gene mutated in X-linked ichthyosis (Ballabio et al., 1987, Yen et al., 1987). This groundbreaking discovery led to the cataloging of more than 500 unique protein-coding genes, underlying 560 different skin and hair abnormalities (Feramisco et al., 2009, Betz et al., 2012). Among skin appendages, the hair follicle (HF) has a remarkably complex architecture, comprised of concentric layers of epithelial cells, which surround and support the highly keratinized, rigid hair shaft. The shaft itself consists of a multicellular cortex and the hair cuticle encased by the three layers of inner root sheath (IRS). The IRS is surrounded by the companion layer and the outer root sheath, which is continuous with the basal layer of the epidermis. With every successive hair cycle, the proliferating matrix cells in the anagen hair bulb differentiate and keratinize, giving rise to the layers of the IRS, as well as the cuticle, cortex, and medulla of the hair (Langbein and Schweizer, 2005). Keratins, desmosomes, and lipids are abundantly expressed in the HF and are essential for maintenance of structural integrity and regulation of apoptosis, stress response, and protein synthesis (Takahashi et al., 2003, Gu and Coulombe, 2007, Kim and Coulombe, 2007). In this review, we will focus on hereditary hair disorders and discuss the studies that linked these disorders to genes encoding structural components of the HF.