Specifically, c-Src’s role in enabling tamoxifen resistance by affecting cellular proliferation through direct phosphorylation of ERα [60,61] or activation of EGFR and STAT5b signaling [73,74,75], the hyperactivation of the PI3K and AKT pathway in cancers, ERK1/2’s phosphorylation of ERα leading to ligand-independent transcription and tamoxifen agonistic effects [76,77,78], and cyclin D1’s regulated interaction with ERα enhancing transcriptional activity all constitute critical facets in the development of tamoxifen resistance [79,80,81]. The gene discussed is ESR1; the disease is cancer.