We systematically exposed the yeast Saccharomyces cerevisiae to a wide array of 101 perturbations and generated a quantitative mass spectrometry-based atlas of early phosphoproteomic responses. Perturbations covered broad classes of environmental, chemical, and drug perturbations and systematically targeted diverse aspects of yeast cell biology. Importantly, most perturbations focused on capturing early signaling responses (5 min treatments), with the reasoning that functional phosphorylation of specific substrates occurs rapidly following stimulation, but promiscuous phosphorylation and confounding changes in transcript and protein abundances takes place more slowly. Large-scale proteomics and phosphoproteomics was enabled by our recently developed R2-P2 (Rapid-Robotic Phosphoproteomics) sample preparation workflow in combination with DIA measurements. In parallel to phosphoproteomic measurements we performed total proteome measurements on the same samples for 30 selected perturbations. This submission includes 126 quantitative DIA-MS raw files that were used for the total proteome analysis.