Oestradiol provides the drive to reproductive cyclicity in female mammals through its ability to stimulate the GnRH surge. In contrast, progesterone can be seen as the 'clutch and brakes' within reproductive cycles, as it can modify the response of the GnRH neurosecretory system to oestradiol. In this regard, progesterone has multiple and sometimes opposing effects on the GnRH neurosecretory system. For example, dependent upon the timing of exposure, progesterone enhances the amplitude of the oestradiol-induced LH (rats) and GnRH surge (within cerebrospinal fluid in sheep, mRNA concentrations in rats), but can also inhibit pulsatile GnRH secretion, and delay or even block expression of the surge (monkeys, rats and sheep). Investigations of the mechanisms of action of progesterone are complicated further by the fact that some of the observed effects of progesterone, such as the ability to block the oestradiol-induced surge, appear to be mediated via several different routes. Consequently, a variety of approaches are needed to advance our understanding of this fundamental reproductive neuroendocrine system. In this context, large animal neuroendocrine models have provided important information about the mechanisms of progesterone action and provide many exciting opportunities for future research.