The transformative processes that prepare the endome- trium for embryo implantation are unique to menstruating species, and are thought to underlie the evolution of menstruation. Although rodent species, which are easy to manipulate, are common experimental models for studies of endometrial receptivity and embryo implanta- tion, findings obtained with these animals often cannot be directly translated to humans. Biological processes that have developed in the human endometrium during the evolution of menstru- ation are specialized versions of processes that are found in other tissues, altered to regulate endometrial biology. Understanding how the human endometrium under- goes controlled and spatially limited tissue destruction, resolution of inflammation, scar-free repair and re- epithelialization followed by regeneration and transfor- mation can inform our understanding of processes that occur in other tissues. In this Review, we describe the remodelling of the endometrium before it becomes receptive for embryo implantation, the dynamic fetal–maternal communi- cation that contributes to successful implantation, the endometrial defects that result in infertility and miscar- riage and the detection and treatment of these disorders. We also identify missing links, both experimental and clinical, which should be investigated to enable progress in the field, and areas where understanding of endo- metrial biology might influence other fields and the development of therapeutics. Evolution of human menstruation Unlike other organs, the human endometrium does not have a single, constant function from birth to death. The endometrium exists to provide a ‘fertile ground’ for implantation of an embryo and development of a highly invasive placenta, which is achieved by an orderly sequence of development and transformation within each menstrual cycle, under the influence of the ovarian steroid hormones 1 . The endometrial cells become terminally dif- ferentiated during each menstrual cycle; in the absence of conception, tissue shedding and regeneration for subse- quent fertile cycles occurs. In menstruating species, decid- ualization is spontaneous, rather than embryo-mediated. Decidualization is the process of the transformation or differentiation of human endometrial stromal fibroblasts to secretory ‘epithelioid’ cells, which occurs under the influence of the hormones oestrogen and progesterone, along with cAMP and local paracrine factors. The evolution of spontaneous decidualization is thought to have occurred when genes that were ances- trally expressed in other organs and tissue systems were expressed in the endometrium. Transposable elements, 1 Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, 3168, Australia. 2 Department of Molecular and Translational Medicine, Monash University, Clayton, 3800, Australia. 3 Department of Physiology, Monash University, Clayton, 3800, Australia. 4 Department of Obstetrics and Gynaecology, Monash University, Clayton, 3800, Australia. 5 Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800, Australia. 6 The Ritchie Centre, Hudson Institute of Medical Research, Clayton, 3168, Australia. 7 Department of Anatomy and Developmental Biology, Monash University, Clayton, 3800, Australia. Correspondence to E.D. evdokia.dimitriadis@hudson. org.au doi:10.1038/nrendo.2016.116 Published online 22 Jul 2016 Fertile ground: human endometrial programming and lessons in health and disease Jemma Evans 1–3 , Lois A. Salamonsen 1,2,4 , Amy Winship 1,2 , Ellen Menkhorst 1,2 , Guiying Nie 1,2,5 , Caroline E. Gargett 4,6 and Eva Dimitriadis 1,2,7 Abstract | The human endometrium is a highly dynamic tissue that is cyclically shed, repaired, regenerated and remodelled, primarily under the orchestration of oestrogen and progesterone, in preparation for embryo implantation. Humans are among the very few species that menstruate and that, consequently, are equipped with unique cellular and molecular mechanisms controlling these cyclic processes. Many reproductive pathologies are specific to menstruating species, and studies in animal models rarely translate to humans. Abnormal remodelling and regeneration of the human endometrium leads to a range of reproductive complications. Furthermore, the processes regulating endometrial remodelling and implantation, including those controlling hormonal impact, breakdown and repair, stem/progenitor cell activation, inflammation and cell invasion have broad applications to other fields. This Review presents current knowledge regarding the normal and abnormal function of the human endometrium. The development of biomarkers for prediction of uterine diseases and pregnancy disorders and future avenues of investigation to improve fertility and enhance endometrial function are also discussed. NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION | 1 REVIEWS ©2016MacmillanPublishersLimited.Allrightsreserved.