S-acylation (also known as palmitoylation) is a major post-translational protein modification in all eukaryotic cells, involving the attachment of fatty acids onto cysteine residues. A variety of structural and signalling proteins are modified in this way, affecting their stability, membrane association and intracellular targeting. The enzymes that mediate S-acylation are encoded by genes belonging to the large (> 20 genes) ZDHHC family. The importance of these enzymes for normal physiological function is highlighted by their links to a diverse range of disease states, including neurological disorders, such as Huntington's disease, schizophrenia and intellectual disability, and diabetes and cancer. The recent study by Yeste-Velasco et al published in the Journal of Pathology highlights a novel tumour suppressor function for the zDHHC family: expression of zDHHC14 is decreased in testicular germ cell tumours, prostate cancer and a variety of other cancer types. This important finding further emphasizes the emerging clinical significance of the zDHHC family of S-acylation enzymes. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.