Proteoglycans are essential constituents of tissue- and organ microenvironments, modulating both the structural scaffolds that surround cells as well as signaling cues that determine cellular phenotype. An important modification of proteoglycans is the sulfation of the monosaccharides that comprise them. Sulfates are added by sulfotransferases and desulfation occurs through the action of sulfatases. In this essay, we examine the biochemistry of a conserved family of desulfating enzymes known as arylsulfatases. A subset of these enzymes mediates the desulfation of proteoglycans. We review the consequences of their aberrant expression in the light of carcinogenesis and carcinomatosis: the dissemination of cancer cells. A closer understanding of their cellular-molecular roles reveals their promise for future strategies for cancer therapy.