Ovarian protection from chemotoxicity is essential for reproductive health. Our objective is to determine the role of ATP-dependent, Multidrug Resistance Transporters (MDRs) in this protection. Previously we identified MDR-dependent cytoprotection from cyclophosphamide in mouse and human oocytes by use of MDR inhibitors. Here we use genetic deletions in MDR1a/b/BCRP of mice to test MDR function in ovarian somatic cells and find that mdr1a/b/bcrp-/- mice had significantly increased sensitivity to cyclophosphamide. Further, estrus cyclicity and follicle distribution in mdrl a/b/bcrp-/- mice also differed from age-matched wildtype ovaries. We found that MDR gene activity cycles through estrus and that MDR-1b cyclicity correlated with 17 beta-estradiol surges. We also examined the metabolite composition of the ovary and learned that the mdrl alb/bcrp-/- mice have increased accumulation of metabolites indicative of oxidative stress and inflammation. We conclude that MDRs are essential to ovarian protection from chemotoxicity and may have an important physiological role in the ovary. (C) 2017 Elsevier Inc. All rights reserved.