Heritable and reversible changes in gene expression can occur without alterations in DNA sequence largely dependent upon the position of a gene within an accessible (euchromatic) chromatin environment. This position effect variegation in Drosophila and S. pombe, and higher order chromatin structure regulation in yeast, is orchestrated by modifier genes of the Su(var) group (e.g. histone deacetylases (HDACs), protein phosphatases) and enhancer E(var) group (e.g. ATP-dependent nucleosome remodeling proteins). Higher order chromatin structure is regulated in part by covalent modification of the N-terminal histone tails of chromatin and histone tails in turn serve as platforms for recruitment of signaling modules that include non-histone proteins such as HP1 and NuRD. As the enzymes governing chromatin structure through covalent modifications of histones (acetylation, methylation, phosphorylation, ubiquitination) can also target non-histone substrates, a mechanism is in place by which epigenetic regulatory processes can affect the function of these alternate substrates. The nuclear receptor (NR) superfamily consists of conserved modular transcriptional regulators. Herein, we review the functional properties of nuclear receptors regulated by their direct acetylation including ligand-dependent activation, cellular growth and apoptosis.