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Epidermal growth factor receptor (Egfr)-driven signaling regulates fundamental homeostatic processes. Dysregulated signaling via Egfr is implicated in numerous disease pathologies and distinct Egfr-associated disease etiologies are known to be tissue-specific. The molecular basis of this tissue-specificity remains poorly understood. Most studies of Egfr signaling to date have been performed or in tissue-specific mouse models of disease, which has limited insight into Egfr signaling patterns in healthy tissues. Here, we carried out integrated phosphoproteomic, proteomic, and transcriptomic analyses of signaling changes across various mouse tissues in response to short-term stimulation with the Egfr ligand Egf. We show how both baseline and Egf-stimulated signaling dynamics differ between tissues. Moreover, we propose how baseline phosphorylation and total protein levels may be associated with clinically relevant tissue-specific Egfr-associated phenotypes. Altogether, our analyses illustrate tissue-specific effects of Egf stimulation and highlight potential links between underlying tissue biology and Egfr signaling output.