The fetomaternal interface, consisting of the maternal decidua and the invading fetal trophoblast, critically regulates placental function and the growth and development of the conceptus. In its broadest sense, decidualization could be viewed as the postovulatory process of endometrial remodeling in preparation for pregnancy, which includes secretory transformation of the uterine glands, influx of specialized uterine natural killer cells, and vascular remodeling. A more restricted definition of the decidual process denotes the morphological and biochemical reprogramming of the endometrial stromal compartment. This differentiation process is dependent entirely on the convergence of the cyclic adenosine monophosphate and progesterone signaling pathways that drives integrated changes at both the transcriptome and the proteome level. As a consequence, decidualizing stromal cells acquire the unique ability to regulate trophoblast invasion, to resist inflammatory and oxidative insults, and to dampen local maternal immune responses. In humans, decidualization of the stromal compartment occurs in the mid-luteal phase of the menstrual cycle, independently of pregnancy. This raises the possibility that biochemical analysis of timed endometrial biopsy samples taken in a nonconception cycle could be informative of subsequent pregnancy outcome.