Sulfatases belong to a highly conserved family of enzymes that catalyze the hydrolysis of O- and N-sulfate esters from a variety of substrates. Among 18 human sulfatase genes identified, about 1/3 are found in lysosomes and serve to remove sulfate from glycosaminoglycans (GAGs), glycopeptides and glycolipids (GLs). The remaining sulfatases are found in microsomes, endoplasmic reticulum (ER), Golgi, at the cell surface, or secreted and are active against hydroxysteroids, heparin or unidentified substrates. Genetic deficiencies of individual sulfatases reveal the critical importance of these enzymes in the metabolism of specific forms of sulfate. Deficiencies of lysosomal sulfatases that act on GAGs and GLs account for mucopolysaccharidoses (MPS) and metachromatic leukodystrophy, respectively. Deficiencies in non-lysosomal sulfatases, arylsulfases C and E, cause X-linked ichthyosis (XLI) and chondrodysplasia punctata (CDPX), respectively.