Uterine leiomyomas are monoclonal tumors. However, the factors involved in their initiation and growth remain poorly understood. The neoplastic transformation of myometrium to leiomyoma likely involves somatic mutations of normal myometrium and the complex interactions of sex steroids and local growth factors. Traditionally, estrogen has been considered the major promoter of myoma growth. The purpose of this review is to highlight the biochemical, histologic, and clinical evidence that supports an equally important role for progesterone in the growth of uterine myomas. Biochemical studies suggest that progesterone, progestins, and the progesterone receptor modulate myoma mitotic activity. Several clinical trials demonstrate that progestins inhibit and/or reverse the ability of hypoestrogenism induced by a gonadotropin-releasing hormone agonist to shrink uterine myomas, suggesting a critical role for progesterone in growth of myomas. A new hypothesis to explain the pathogenesis of myomas is presented.