The invention of the contraceptive pill in the 1960s was a watershed achievement of reproductive endocrinology. Its use expanded rapidly with a vast array of benefits for Women and society. However, as a daily exogenous hormone treatment, there are drawbacks of this existing technology that are becoming more clearly understood through recent randomised controlled trials and epidemiological studies. Among these are increased risk of venous thromboembolism and a probable doubling of breast cancer risk attributed to the progestogen component of all oral contraceptive pills. Remarkably, environmental contamination is another unintended drawback arising from the very widespread use of the pill. The very high levels of progesterone administered act to prevent gonadotropin surge secretion by the pituitary. This mode of contraceptive action accomplished by progestin pills is ideal as ovulation is prevented meaning that fertilisation and implantation are not possible. Importantly, progesterone is also required in the ovary to mediate ovulation. We have shown that Progesterone Receptor null mice completely fail to ovulate and we are continuing to interrogate the molecular requirements for mammalian ovulation in this and other model systems. Through establishing a deeper understanding of the mechanism of ovulation at the ovarian level, new molecular targets are emerging that offer the potential to block ovulation through a non-hormonal drug treatment therapy. This strategy can offer potential advantages including; targeting ovulation directly without off target actions, eliminating the risks of side effects while retaining the known benefit for ovarian cancer risk and efficacy with a single monthly administration reducing the dose amount and risk of missed doses that are unavoidable with reproductive hormone treatment. Among the strategies we are investigating are targeting protease enzymes and other tissue remodelling factors obligatory for ovarian follicle rupture and release of the oocyte, or factors which mediate the expansion of the cumulus oocyte complex during the periovulatory phase.