The histone acetyltransferase MOF is central to the process of dosage compensation complex in Drosophila, which assures that the transcriptional activity of large parts of the male X chromosome is enhanced by about two-fold. Inactivation of the acetyl transferase activity of MOF is lethal to affected male flies. MOF belongs to the MYST family of acetylases that are involved in a wide variety of cellular processes. One characteristic structural feature of this family is the presence of a CCHC zinc finger adjacent to their acetyl-CoA binding motif. Structure-function analyses of several family members suggest that this region is important for enzymatic activity. Our detailed characterization of MOF shows that the CCHC-type zinc finger is required for interaction with the histone substrate and hence catalytic activity.