Obesity in women is associated with systemic insulin resistance and metabolic syndrome, as well as increased insulin and triglyceride in the ovarian follicular fluid surrounding the developing oocyte, and reduced conception rates. Obesity in females also alters fetal development during pregnancy and permanently programs the metabolism of offspring; however mechanisms responsible and whether they are preventable is not clear. Our studies in mice show that insulin resistance and hyperlipidemia lead to endoplasmic reticulum stress in the oocyte complex and altered mitochondrial activity in oocytes. In vitro fertilization of oocytes from obese mice demonstrates their impaired developmental potential and marked mtDNA loss by the blastocyst stage. Subsequently, fetuses from obese oocytes were heavier than controls and had reduced liver, heart and kidney mtDNA content. Treatment of the obese females with ER stress inhibitor salubrinal or the chaperone inducer BGP-15 immediately prior to IVF normalized oocyte mitochondrial activity as well as subsequent blastocyst development, fetal weight and fetal tissue mtDNA content. These results demonstrate that obesity in mothers imparts a legacy of mitochondrial loss in offspring, that is due to cellular stress during oocyte maturation but that is preventable prior to conception.