Clomiphene citrate (CC) is the most commonly used oral agent for the induction of ovulation. It is a nonsteroidal selective estrogen receptor modulator that has predominant antiestrogenic action resulting in long-lasting estrogen receptor depletion. Side effects include antiestrogenic effects systemically and on the endometrium and cervical mucous. Letrozole is a potent, nonsteroidal, aromatase inhibitor, originally used for postmenopausal breast cancer therapy, at present its only registered indication. We hypothesized that letrozole could mimic the action of CC without depletion of estrogen receptors. As there is no estrogen receptor antagonism, antiestrogenic effects such as poor cervical mucus and thin endometrium are not expected with aromatase inhibitor treatment. In addition, because estrogen receptors in the brain are not depleted, normal negative feedback occurs with letrozole and generally results in monoovulation. We and others have demonstrated the success of aromatase inhibition in inducing ovulation in women with polycystic ovarian syndrome. Letrozole may be very effective for ovulation induction and pregnancy in cases of CC resistance. When used together with follicle-stimulating hormone (FSH) injections, letrozole resulted in a significant reduction in the FSH dose needed for controlled ovarian hyperstimulation. Aromatase inhibitors likely increase ovarian sensitivity to FSH, and may be useful in poor responders and in women undergoing ovarian stimulation for in vitro fertilization. The safety of letrozole in pregnancy outcome studies has been demonstrated by examination of spontaneous pregnancy loss, multiple pregnancy rates, and congenital anomalies compared with a control group of infertility patients treated with CC. In addition, new data suggest that CC may result in cardiac anomalies and other birth defects and in low birth weight babies. We believe aromatase inhibitors are acceptable alternatives to CC as first line oral agents for ovulation induction or controlled ovarian stimulation.