MOF (males absent on the first) was initially discovered as a dosage compensation factor that regulates the epigenetic acetylation of histone H4 lysine 16. In this issue, Sheikh et al. demonstrate that MOF expression is not required for normal kidney tissue function but is required for maintaining transcriptional regulation under conditions of stress. This work along with results from previous investigators highlights the importance of the cell lineage-chromatin modification interaction in determining transcriptional programs and physiological outcomes under normal and stress conditions.