p63 plays a key role in epithelial development in various organs, being expressed in myoepithelial cells and in basal cells of stratified epithelia. In the female genital tract, p63 is expressed in the basal and parabasal cells of mature cervical, vaginal and vulval squamous epithelium, and also in cervical reserve cells at the transformation zone and in immature metaplastic and atrophic cervical squamous epithelium. In this review, the diagnostic utility of p63 immunohistochemical staining in various pathologic scenarios within the female genital tract is discussed. Cervical microglandular hyperplasia is p63 positive with a characteristic subcolumnar location due to expression in reserve cells. There is increased expression in cervical intraepithelial neoplasia, in accordance with the degree of dysplasia. One of the most useful applications of p63 is in the evaluation of problematic cervical carcinomas; most squamous carcinomas exhibit diffuse nuclear immunoreactivity whereas most adenocarcinomas and neuroendocrine carcinomas are negative or focally positive. In conjunction with neuroendocrine markers, p63 is useful in distinguishing between a squamous carcinoma and a small cell or large cell neuroendocrine carcinoma. In the normal endometrium, a population of p63-positive cells is present which may act as a stem cell population and which is increased in various forms of metaplasia. Placental site nodule and epithelioid trophoblastic tumor (lesions derived from chorionic-type intermediate trophoblast) are usually p63 positive whereas placental site reaction and placental site trophoblastic tumor (lesions derived from implantation site intermediate trophoblast) are usually negative; thus, p63 may be useful in the diagnostic algorithm of trophoblastic lesions. p63 positivity in ovarian epithelial tumors is uncommon and largely restricted to squamous and transitional neoplasms, including benign and borderline Brenner tumor. p63 is also positive in cervical transitional metaplasia, Walthard rests, vulval Paget disease secondary to an underlying urothelial malignancy, tubulosquamous polyp of the vagina, and ectopic prostatic tissue in the cervix.