Recent studies strongly suggest that matrix metalloproteinases (MMPs) play a key role in the initiation of menstrual bleeding in the human endometrium upon the fall of ovarian steroid serum concentrations by inducing the degradation of the extracellular matrix of this mucosa. MMPs are also involved in abnormal endometrial bleeding and have been identified in endometriotic foci. In all cases, they are associated with areas of extracellular matrix breakdown. This paper reviews the literature on the regulation by estradiol and progesterone of the expression and activation of MMPs, and of the expression of their tissue inhibitors (TIMPs), (i) in the endometrium in situ during normal cycle, (ii) during artificial cycles in spayed monkeys, and (iii) in cultures of endometrial explants or purified cells. Whereas progesterone consistently decreases the activity of endometrial MMPs, its effects vary in intensity, duration, and pattern between MMPs as well as among experimental systems. The contribution and limitations of the various investigations are therefore discussed. The focal heterogeneity points to additional local controls of the expression and activation of MMPs in human endometrium, acting beyond the general inhibitory role of progesterone, for example, by cytokines. Focal changes in type or abundance of sex steroid receptors also could be responsible for spatial variation in the expression of MMPs in the endometrium and endometriotic lesions.