Epidermal growth factor receptors (EGFR, HER2, HER3) activate signal transduction pathways involved in cancer proliferation, apoptosis, differentiation, metastasis, and angiogenesis. Their overexpression and activation are associated with unfavorable prognosis of cancer patients. Therefore, they are attractive targets for cancer therapy. Due to the development of drug resistance, therapeutic monoclonal antibodies and synthetic small molecule tyrosine kinase inhibitors directed against EGFR family members may fail with fatal consequences for cancer patients. Medicinal plants raised considerable interest during the past years as valuable resources to develop novel treatment therapies targeting epidermal growth factor receptors and their downstream signal transduction pathways. The present review gives an overview of isolated phytochemicals that inhibit these signaling routes. Inhibitors have been described that down-regulate the mRNA or protein expression of EGFR, HER2, or HER3 or inhibit the phosphorylation of these receptors and/or their downstream signaling kinases. Remarkably, a wealth of in vivo experiments complemented in vitro data, indicating that natural products are also active in living animals bringing this research concept closer to clinical applicability. The combination of receptor-inhibiting natural product with standard anticancer drugs frequently caused increased or even synergistic tumor inhibition in vitro and in vivo. It deserves further evaluation, if and how epidermal growth factor receptor-targeting natural products can be integrated into clinical oncology as well as to define their role for more tumor-specific and individualized tumor therapies.