The family of epidermal growth factor receptors (EGFRs) is overexpressed in many gynecologic malignancies. Extensive preclinical studies of these receptors demonstrate that they play an important role in supporting the growth of a wide variety of malignancies and that interruption of receptor function or signaling from these receptors leads to inhibition of tumor growth or in certain cases tumor regression. Recently, many therapeutic agents targeting this receptor have entered the clinic and phase II clinical studies have demonstrated activity in lung cancer, colon cancer, and head and neck malignancies. Phase II trials of both small molecule inhibitors of EGFR and antibody-based inhibitors are underway in both cervical and ovarian cancer and emerging data suggests that their activity in unselected women with advanced gynecologic malignancies is very modest. Recently, molecular analysis of lung cancers has identified that the response to small molecule inhibitors of EGFR is highly correlated with activating mutations within the EGFR. It is possible that these agents will be highly effective in a small subset of patients with gynecologic malignancies whose tumors are dependent on EGFR signaling, perhaps through an activating mutation in EGFR or its downstream pathway. Until additional research can identify the subset of patients most likely to benefit from this targeted therapy, treatment for women with gynecologic malignancies with EGFR inhibitors should be limited to investigational trials. It is critical that these trials have access to tissue of responding and nonresponding patients so to determine the rational use of these agents in the treatment of gynecologic malignancies.