The philosophy of Yin (阴) and Yang (阳) formed in ancient China describes a subtle, complementary, and sometimes intimate relationship between two opposites. This thousands of years old philosophy is, however, perfectly suited to describe the relationship between p53 and MDM2, whose genes evolved hundreds of millions of years ago. p53 and MDM2 are found in both (some) invertebrate and (all) vertebrate organisms, and mutually live with and almost always depend on each other in most multi-cellular organisms, including humans. The MDM2 protein (also called HDM2 for its human homologue) is a natural ‘killer’ of the p53 protein, as it prohibits p53 functions by promoting its breakdown and/or inhibiting its activity, whereas p53 acts as a transcriptional factor that can rouse the production of MDM2 at its mRNA level, hence forming a negative feedback axis. When p53 is activated, it can execute its functions as a ‘guardian of the genome’ by either triggering the expression of genes important for the regulation of cell growth and proliferation, cellular senescence, apoptosis, DNA repair, ferroptosis, cell metabolism, angiogenesis, and autophagy, or sometimes even directly inducing apoptosis. The sum of these p53-regulated events either halts cell growth or leads to cell death, essential for both normal organism development and protection from cancers. Thus, p53, which was discovered by Arnold Levine and David Lane in 1979, can be considered as ‘Yin’. By sharp contrast, MDM2 can overcome these p53-dependent functions detrimental to cell growth and proliferation as a physiological negative modifier of p53, allowing cells to live. Hence, MDM2 can be considered as ‘Yang’, as it plays an almost exactly opposite role to that of p53. Intensive studies of this p53−MDM2 negative feedback axis over the past quarter century have unveiled a beautiful molecular ‘tale’ about the delicate balance of Yin and Yang.