The Forkhead boxO (FOXO) transcription factors regulate multiple cellular functions. FOXO1 and FOXO3 are highly expressed in granulosa cells of ovarian follicles. Selective depletion of the Foxo1 and Foxo3 genes in granulosa cells of mice reveals a novel ovarian-pituitary endocrine feedback loop characterized by: 1) undetectable levels of serum FSH but not LH, 2) reduced expression of the pituitary Fshb gene and its transcriptional regulators, and 3) ovarian production of a factor(s) that suppresses pituitary cell Fshb expression. Equally notable, and independent of FSH, microarray analyses and quantitative PCR document that depletion of Foxo1/3 alters the expression of specific genes associated with follicle growth vs. apoptosis by disrupting critical and selective regulatory interactions of FOXO1/3 with the activin or bone morphogenetic protein 2 (BMP2) pathways, respectively. As a consequence, both granulosa cell proliferation and apoptosis were decreased. These data provide the first evidence that FOXO1/3 divergently regulate follicle growth or death by interacting with the activin or BMP pathways in granulosa cells and by modulating pituitary FSH production.