Since its discovery in 1979, p53 has become the focus of intensive cancer-based research in laboratories around the world. The p53 protein mediates critical cellular functions including the response to genotoxic stress, differentiation, senescence, and apoptosis, and has been shown to be mutated in a large proportion of human cancers. These observations led many to speculate that targeting the p53 pathway would result in the development of successful anti-cancer treatments. In spite of this, 30 years later, p53 has yet to fulfill this promise. However, new insights into small molecule combination therapies, microRNA regulation, structuring of clinical trials, and potential involvement in stem cell regulation may help p53 reach its potential.