Here, we harness genome-wide approaches to elucidate the mechanism by which Cas5 orchestrates transcriptional changes in response to cell wall perturbation. We identify an unexpected role for Cas5 in coupling cell cycle dynamics to cell wall stress responses, and determine that Cas5 regulates distinct transcriptional programs under basal and stress conditions. We discover that Cas5 is activated by the type I protein phosphatase Glc7 in response to cell wall stress, and it regulates cell wall homeostasis in part through its interaction with Swi4-Swi6 cell cycle box-binding factor (SBF) complex members, Swi4 and Swi6. Finally, we describe a role for Cas5 in orchestrating nuclear division. Our work provides insight into cellular reprogramming in response to cell wall stress, and establishes regulatory circuitry that couples stress response, cell cycle regulation, and drug resistance.