Macroautophagy (autophagy hereafter) captures, degrades, and recycles intracellular components to maintain metabolic homeostasis and protein and organelle quality control. Autophagy thereby promotes survival in starvation and prevents tissue degeneration. There is an important relationship between autophagy and p53. Autophagy suppresses p53 and also p53 activates autophagy. The suppression of p53 by autophagy is important for tumor promotion and likely also for preventing tissue degeneration. Alternatively, the activation of autophagy by p53 suggests that autophagy is part of the protective function of p53. Uncovering the underlying mechanisms of the autophagy-p53 reciprocal functional interaction and has important implications for human disease and treatment.