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A coregulated module of genes (“regulon”) can have evolutionarily conserved expression patterns and yet have diverged upstream regulators across species. For instance, the ribosomal genes regulon is regulated by the transcription factor (TF)TBF1inCandida albicans, while inSaccharomyces cerevisiaeit is regulated byRAP1. Only a handful of such rewiring events have been established, and the prevalence or conditions conducive to such events are not well known. Here, we develop a novel probabilistic scoring method to comprehensively screen for regulatory rewiring within regulons across 23 yeast species. Investigation of 1,713 regulons and 176 TFs yielded 5,353 significant rewiring events at 5% false discovery rate (FDR). Besides successfully recapitulating known rewiring events, our analyses also suggest TF candidates for certain processes reported to be under distinct regulatory controls inS. cerevisiaeandC. albicans, for which the implied regulators are not known: 1) Oxidative stress response (Sc-MSN2to Ca-FKH2) and 2) nutrient modulation (Sc-RTG1to Ca-GCN4/Ca-UME6). Furthermore, a stringent screen to detect TF rewiring at individual genes identified 1,446 events at 10% FDR. Overall, these events are supported by strong coexpression between the predicted regulator and its target gene(s) in a species-specific fashion (>50-fold). Independent functional analyses of rewiring TF pairs revealed greater functional interactions and shared biological processes between them (P= 1 × 10−3).Our study represents the first comprehensive assessment of regulatory rewiring; with a novel approach that has generated a unique high-confidence resource of several specific events, suggesting that evolutionary rewiring is relatively frequent and may be a significant mechanism of regulatory innovation.