Histone acetylation regulates most DNA transactions and is dynamically controlled by highly conserved enzymes. The only essential histone acetyltransferase (HAT) in yeast, Esa1, is part of the 1MDa NuA4 complex, which plays pivotal roles in both transcription and DNA damage repair. NuA4 has the unique capacity to acetylate histone targets located several nucleosomes away from its recruitment site. Neither the molecular mechanism of this activity nor its physiological importance are known. Furthermore, a high-resolution model for holo-NuA4 is lacking. Here we report the structure of the yeast NuA4 complex with its core resolved at 3.4 Å resolution. Three subunits, Epl1, Eaf1, and Swc4, intertwine to form a stable platform that coordinates all other modules. The HAT module is firmly anchored into the core while retaining the ability to stretch out over a long distance. We provide structural, biochemical and genetic evidence to demonstrate that an unfolded region of the Epl1 subunit is critical for this long-range activity, which we show to be essential for viability and maintenance of acetylated H4 levels in yeast. Our work lays the foundations for a mechanistic understanding of NuA4 regulatory role and elucidates how its essential long-range activity is attained.