Epigenetic transcriptional states are controlled in large part through chromatin modification. Epigenetically silenced regions in yeast were first recognized to be regulated by the SIR1‐4 genes. Of these, SIR2 and its homologs are now known to encode NAD‐dependent protein deacetylases (NAD‐DACs) with connections to processes as diverse as metabolic sensing, cellular aging, and pathogenic virulence. Since the discovery of the SIR genes, a growing number of other epigenetic modifiers have been identified, many of which have distinct catalytic activities. Some of these directly modify histones and other substrates to influence transcription, whereas others have clear roles in chromatin assembly, remodeling, repair and recombination. Mutational analyses reveal that many of these epigenetic modifiers at first blush have seemingly minor roles in normal cellular physiology. However, several of them functionally interact and their cumulative loss can lead to cell death. Our studies of the NAD‐DACs, acetyltransferases (ATs) and methyltransferases (MTs) have uncovered new epigenetic modifiers with previously unsuspected roles in transcriptional silencing. Critical interactions will be defined between ATs and MTs, and an enhancer that results in stress‐induced lethality of sir2Δ mutants.