ABSTRACTPrimordial follicles are formed perinatally in mammalian ovaries and at birth represent the lifetime complement of germ cells. With cyclic periodicity, cohorts enter into a growth phase that culminates in ovulation of mature eggs, but little is known about the regulatory cascades that govern these events. FIGα, a transcription factor implicated in postnatal oocyte-specific gene expression, is detected as early as embryonic day 13. Mouse lines lacking FIGα were established by targeted mutagenesis in embryonic stem cells. Although embryonic gonadogenesis appeared normal, primordial follicles were not formed at birth, and massive depletion of oocytes resulted in shrunken ovaries and female sterility. Figα (the gene for FIGα) null males have normal fertility. The additional observation that null females do not express Zp1, Zp2 or Zp3 indicates that FIGα plays a key regulatory role in the expression of multiple oocyte-specific genes, including those that initiate folliculogenesis and those that encode the zona pellucida required for fertilization and early embryonic survival. The persistence of FIGα in adult females suggests that it may regulate additional pathways that are essential for normal ovarian development.