The tumor suppressor protein p53 is a redox-active transcription factor that organizes and directs cellular responses in the face of a variety of stresses that lead to genomic instability. One of the most important questions in the study of p53 is how selective transactivation of certain p53 target genes is achieved. Reactive oxygen species (ROS), generated by cells as products or by-products, can function either as signaling molecules or as cellular toxicants. Cellular generation of ROS is central to redox signaling. Recent studies have revealed that each cellular concentration and distribution of p53 has a distinct cellular function and that ROS act as both an upstream signal that triggers p53 activation and a downstream factor that mediates apoptosis. Here, we examine the newly discovered role of p53 in regulating cellular ROS generation and how ROS modulate selective transactivation of p53 target genes. The focus is on interlinks between ROS and p53.