Based on the existing reports of potential cellular and molecular mechanisms of p53 activation in enhancing innate immunity, our knowledge of the cooperativity between innate and adaptive immunity, and some of our unpublished observations, we discuss here the contribution of various cellular and molecular pathways to p53 activation-mediated immune activation and potential development of targeting the p53 pathway as a novel immunotherapy strategy for cancer control and clearance. The gene discussed is TP53; the disease is cancer.