P53 up-regulated modulator of apoptosis (PUMA), a pro-apoptotic BCL-2 homology 3 (BH3)-only member of the BCL-2 family, is a direct transcriptional target of P53 that elicits mitochondrial apoptosis under treatment with radiation and chemotherapy. It also induces excessive apoptosis in cardiovascular and/or neurodegenerative diseases. PUMA has been found to play a critical role in ovarian apoptosis. In the present paper, we review the progress of the study in PUMA over the past two decades in terms of its inducement and/or amplification of programmed cell death and describe recent updates to the understanding of both P53-dependent and P53-independent PUMA-mediated apoptotic pathways that are implicated in physiology and pathology, including the development of the ovary and cardiovascular and neurodegenerative diseases. We propose that PUMA may be a key regulator during ovary development, provide a model for PUMA-mediated apoptotic pathways, including intrinsic and extrinsic apoptotic pathways.