Cyclophosphamide (CPM), a part of most cancer treatment regimens, has demonstrated high gonadal toxicity in females. Initially, CPM is believed to damage the ovarian reserve by premature activation of primordial follicles, for the fact that facing CPM damage, primordial oocytes show the activation of PTEN/PI3K/AKT pathways, accompanied by accelerated activation of follicle developmental waves. Meanwhile, primordial follicles are dormant and not considered the target of CPM. However, many researchers have found DNA DSBs and apoptosis within primordial oocytes under CPM-induced ovarian damage instead of premature accelerated activation. A stricter surveillance system of DNA damage is also thought to be in primordial oocytes. So far, the apoptotic death mechanism is considered well-proved, but the premature activation theory is controversial and unacceptable. The connection between the upregulation of PTEN/PI3K/AKT pathways and DNA DSBs and apoptosis within primordial oocytes is also unclear. This review aims to highlight the flaw and/or support of the disputed premature activation theory and the apoptosis mechanism to identify the underlying mechanism of CPM's injury on ovarian reserve, which is crucial to facilitate the discovery and development of effective ovarian protectants. Ultimately, this review finds no good evidence for follicle activation and strong consistent evidence for apoptosis.© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.