Many organs are capable of extensive repair after damage, by known mechanisms that can be exploited clinically. By contrast, in spite of the central importance of the ovary for human fertility and women’s health, many important aspects of its basic biology, including its capacity for repair, are poorly understood. For example, ovarian longevity is dependent on the supply of follicles, but how the balance between quiescent versus developing follicles is regulated has not yet been determined. Likewise, it was recently discovered that adult and fetal granulosa cells arise at independent stages from LGR5+ progenitors in the neonatal ovarian surface epithelium (OSE) -‐ but whether these LGR5+ cells can renew adult follicles is not known. Finally, in many organs, vascular, neuronal, and immune cells play critical roles in repair, but their functions in the ovary have not been fully investigated. We recently developed a novel murine model of chemotherapy (CTx)-‐induced infertility and premature ovarian failure (POF). Surprisingly, when we grafted a fragment of a normal ovary to one ovary of a CTx-‐ treated female, grafted females produced multiple litters over the next 5 months, containing normal pups derived from both the host and the donor. Histology revealed that only the grafted ovary was rescued, while the contralateral side degenerated and all follicles were lost. These experiments show that the ovary can be rescued after CTx through signals from a normal ovary. The primary goals of this project are to characterize the mechanisms underlying the loss of all follicles after CTx, and to determine how a small graft from a healthy ovary rescues the host organ system. Our experiments are designed to test three alternative, or complementary, mechanisms of rescue. First, preliminary results suggest that it is the rapidly dividing granulosa cells in growing follicles, and not oocytes, that are the primary target of DNA-‐damaging chemotherapeutic drugs. In Aim 1 we will test whether the loss of granulosa cells in growing follicles leads to de-‐repression of quiescent granulosa cells in primordial follicles, resulting in exhaustion of the reserve pool or “follicle burn out”, and whether signals from the graft block this depletion. In Aim 2, we will test whether LGR5+ cells in the OSE respond to damage and give rise to new granulosa cells after grafting. CTx may interfere with this regenerative activity while signals from the graft may promote it. In Aim 3, we will test whether the graft enhances signals from neural, vascular, or immune cells that can promote repair after injury. Results may lead to new therapies and change the prognosis for women undergoing POF from different causes.