Ovarian primordial follicles do not regenerate and proliferate in vivo, and their number decreases with aging as well as with certain pathogeneses. When the number of residual follicles decreases to a threshold level, the initial step of follicle development, namely, the activation of dormant follicles is disturbed and subsequent follicle growth is suppressed resulting in anovulation and amenorrhea. Because the exact mechanisms of the activation of dormant primordial follicles still remain to be determined, we focused on intracellular signaling in the activation process and succeeded in activating those follicles through the activation of PI3K-Akt-Foxo3 pathway (IVA; in vitro activation). Based on the success of IVA, we performed clinical studies to generate mature oocytes from patients with primary ovarian insufficiency, who had few residual follicles in their ovaries, and we have reported successful pregnancies and a birth following IVA. In this review, I show our IVA approach and discuss future possibilities for the infertility treatment in patients with diminished ovarian reserve.