The endometrium is a unique and remarkable tissue characterized by a constant regeneration activity and this has been speculative for scientists, regarding its mechanism, regulatory factors, and their significance for fertility and endometrial pathology. Relatively recent scientific progresses due to genomics, proteomics, and transcriptomics have changed the knowledge in respect with endometrial regeneration and uterine-derived diseases. Our review is designed to highlight the recent progresses in understanding the endometrial physiology and its alterations involvement in uterine-derived diseases, addressing the current paradigm regarding endometrial regeneration, based on endometrial regenerative cells. In an attempt to explain the complex process of endometrial regeneration, different mechanisms have been proposed during time, from proliferation of basal glandular cells, to mesenchymal-epithelial transition, and lately to differentiation of stromal cells, based on endometrial regenerative cells or stem cells. Their unlimited potential of reconstruction of any type of tissue has been demonstrated and is currently in different trial stages in cell-based therapies of regenerative medicine, opening promising perspectives in severe or lethal diseases, by exploitation of stem cells. Currently, beside uterine acquired diseases and infertility, endometrial stem cells have been tested in a large spectrum of clinical applications. The great potential of endometrial cells for cell therapies arise from their accessibility, completely xeno-free derivation, allogenic use, possibility of large-scale therapeutic doses production, safety, reproducibility, and chance to overcome the drawbacks associated with autologous therapies. In order to overcome hostile environment of an injured tissue, the association of endometrial stem cells with other cells or added medium opens the perspective of specific combination available as standardized therapeutic means in the next future.