O-linked glycosylation of proteins begins with the attachment of a single N-acetylgalactosamine (GalNAc) residue to a serine or threonine residue of the polypeptide and glycosylation of proteins can dramatically change their properties, interactions and activities. This initial attachment is catalysed by members of a family of 20 isoenzymes, the UDP-N-α-D-galactosamine: polypeptide N-acetylgalactosaminyltransferases or ppGalNAc-Ts. Why such a large family of isoenzymes are required to perform, apparently, a single function has been the subject of intense interest. The ppGalNAc-Ts, in fact, have overlapping, but distinct, substrate specificities and are differentially expressed in different cells and tissues and under different conditions of differentiation and development, allowing subtle and complex control of cellular glycosylation. Intriguingly, there is a growing body of evidence showing that altered expression of members of this transferase family are a common feature of many types of cancer and, crucially, that the resulting aberrant glycosylation has functional effects. Here, we review what is known of the expression and distribution of these intriguing transferases in health and in malignancy and, for the first time, bring together what is known of the functional and molecular effects of their disregulation in each step of the complex cascade of cancer metastasis.