Chromatin structure is important for the compaction of eukaryotic genomes, thus chromatin modifications play a fundamental role in regulating many cellular processes. The coordinated activities of various chromatin-remodelling and -modifying complexes are crucial in maintaining distinct chromatin neighbourhoods, which in turn ensure appropriate gene expression, as well as DNA replication, repair, and recombination. SWR1-C is an ATP-dependent histone deposition complex for the histone variant H2A.Z, whereas NuA4 is a histone acetyltransferase for histones H4, H2A, and H2A.Z. Together the NuA4 and SWR1-C chromatin-modifying complexes alter the chromatin structure through 3 distinct modifications in yeast: post-translational addition of chemical groups, ATP-dependent chromatin remodelling, and histone variant incorporation. These 2 multi-protein complexes share 4 subunits and function together to regulate the circuitry of H2A.Z biology. The components and functions of both multi-protein complexes are evolutionarily conserved and play important roles in multi-cellular development and cellular differentiation in higher eukaryotes. This review will summarize recent findings about NuA4 and SWR1-C and will focus on the connection between these complexes by investigating their physical and functional interactions through eukaryotic evolution.