This chapter presents methods for interrogating the involvement of p53 in signaling to apoptosis, autophagy, and senescence. The well-known association of p53 with the stress response to chemotherapy and radiation is the basis for presenting these approaches. The development of quantitative and efficient in vitro assays has enabled researchers to overcome the limitations of previous methodologies. This chapter provides up-to-date procedures relating to the molecular networks in which the p53 protein has been shown to play a central role that allows damaged cells either to adapt to stress (autophagy and/or senescence) or to progress towards programmed cell death (apoptosis).