The clear importance of p53 as a tumour suppressor protein has propelled decades of intense research focused on understanding the functions of p53 and attempting to harness this knowledge for patient benefit. p53 plays a pivotal role in the ability of cells to sense and respond to stress—functions that contribute not only to limitation of cancer development, but also to modulating numerous other aspects of health and disease. Although the canonical activities of p53 relate to the elimination of damaged cells through cell death or senescence, more recent work has highlighted a role for p53 as a guardian of cell survival and facilitator of adaptation during metabolic stress. These emerging metabolic features of p53 activity are proving to be crucial for many of its essential functions.