Histone modifications such as acetylation, methylation and phosphorylation have been implicated in fundamental cellular processes such as epigenetic regulation of gene expression, organization of chromatin structure, chromosome segregation, DNA replication and DNA repair. Males absent on the first (MOF) is responsible for acetylating histone H4 at lysine 16 (H4K16) and is a key component of the MSL complex required for dosage compensation in Drosophila. The human ortholog of MOF (hMOF) has the same substrate specificity and recent purification of the human and Drosophila MOF complexes showed that these complexes were also highly conserved through evolution. Several studies have shown that loss of hMOF in mammalian cells leads to a number of different phenotypes; a G2/M cell cycle arrest, nuclear morphological defects, spontaneous chromosomal aberrations, reduced transcription of certain genes and an impaired DNA repair response upon ionizing irradiation. Moreover, hMOF is involved in ATM activation in response to DNA damage and acetylation of p53 by hMOF influences the cell's decision to undergo apoptosis instead of a cell cycle arrest. These data, highlighting hMOF as an important component of many cellular processes, as well as links between hMOF and cancer will be discussed.