Innate immunity is the first line of defense against invading pathogens. Changes in both metabolism and chromatin accessibility contribute to the shaping of these innate immune responses, and we are beginning to appreciate that cross-talk between these two systems plays an important role in determining innate immune cell differentiation and function. In this review we focus on acetylation, a post-translational modification important for both regulating chromatin accessibility by modulating histone function, and for functional regulation of non-histone proteins, which has many links to both immune signaling and metabolism. We discuss the interactions between metabolism and acetylation, including the requirement for metabolic intermediates as substrates and co-factors for acetylation, and the regulation of metabolic proteins and enzymes by acetylation. Here we highlight recent findings, which demonstrate the role that the metabolism-acetylation axis has in coordinating the responses of innate immune cells to the availability of nutrients and the microenvironment.