The action exerted by estrogens in normal and neoplastic tissues is mainly mediated by the classical estrogen receptors (ER)α and ER. However, recent studies have also indicated that GPR30/GPER mediates rapid effects induced by estrogens through ERK activation and gene transcription. Moreover, GPER overexpression was associated with an aggressive phenotype of estrogen-sensitive tumors, suggesting that the regulation of GPER may be involved in cancer progression. In this context, an EGFR-dependent up-regulation of GPER expression was shown in both ERα-negative and positive cancer cells, providing additional evidence that estrogen and growth factor signaling cooperate in the amplification of mitogenic stimuli in different cell lines. In addition, the physical interaction between either GPER and EGFR or GPER and ERα generated a multi-protein complex, further supporting the functional cross-talk elicited by these receptors in the progression of estrogen-sensitive tumors. Numerous studies have evidenced that the EGFR-mediated transduction pathway contributes to the tamoxifen resistance in patients with breast cancer. As the 4-hydroxytamoxifen binds to and activates GPER, the EGFR-dependent GPER induction observed in tamoxifen-resistant breast cancer cells might be included among the mechanisms involved in the tamoxifen failure in breast malignancy. Surprisingly, an important hallmark of cancer growth, resistance to chemotherapy and decreased survival of patients, such as hypoxia, was demonstrated to regulate GPER expression in breast tumor cells and even in cardiomyocytes. Hence, GPER regulation may be included in the mechanisms leading to the adaptation to hypoxia in cancer and in the cardiovascular system.