Many activities within a cell must be intimately coordinated with its metabolic state. Understanding these connections to metabolism is critical to deciphering the regulation of a variety of cellular processes. However, despite intensive research in these areas, the precise mechanisms by which a cell monitors its metabolic state remain controversial and poorly understood. Herein, we discuss the thesis that intracellular levels of the metabolite acetyl-CoA represent a critical gauge of cellular metabolic state, which is cleverly monitored by the cell through dynamic acetylation modifications to direct a variety of outputs connected to energy metabolism, cell growth, and survival.