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. Here, TP53 is linked to neurodegenerative disease.