Epidermal Growth Factor Receptor (EGFR) enacts major roles in the maintenance of epithelial tissues. However, when EGFR signaling is altered, it becomes the grand orchestrator of epithelial transformation, and hence one of the most world-wide studied tyrosine kinase receptors involved in neoplasia, in several tissues. In the last decades, EGFR-targeted therapies shaped the new era of precision-oncology. Despite major advances, the dream of converting solid tumors into a chronic disease is still unfulfilled, and long-term remission eludes us. Studies investigating the function of this protein in solid malignancies have revealed numerous ways how tumor cells dysregulate EGFR function. Starting from preclinical models (cell lines, organoids, murine models) and validating in clinical specimens, EGFR-related oncogenic pathways, mechanisms of resistance, and novel avenues to inhibit tumor growth and metastatic spread enriching the therapeutic portfolios, were identified. Focusing on non-small cell lung cancer (NSCLC), where EGFR mutations are major players in the adenocarcinoma subtype, we will go over the most relevant discoveries that led us to understand EGFR and beyond, and highlight how they revolutionized cancer treatment by expanding the therapeutic arsenal at our disposal.