Human reproduction is characterized by a high degree of embryo wastage, which is largely ascribed to a high prevalence of embryo aneuploidy. It is proposed that maternal strategies have evolved that prevent inappropriate investment in invasive, but poorly viable embryos. Key to this is the emerging concept of the endometrium as biosensor, first identified in human in vitro embryo/decidualized stromal cell coculture systems and recently confirmed in an in vivo mouse model. In this review, the growing supporting experimental evidence for the biosensor component of decidualized endometrium is outlined, and recent insights into the nature of the embryo-derived signal detected by the endometrium and the biological processes by which this signal is thought to be converted into a go or no-go endometrial response are described. Finally, the clinical implications of this new paradigm of the choosy uterus are addressed.