Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has been shown to act as a tumor suppressor whose function includes important roles in regulating oxidative stress, indicating a potential role in oxidative damage-associated cancer. Accumulating evidence has revealed that PTEN also acts as a pivotal determinant of cell fate, regarding senescence and apoptosis, which is mediated by intracellular reactive oxygen species (ROS) generation. Cells are continuously exposed to ROS, which represent mutagens and are thought to be a major contributor to cancer and the aging process. Therefore, cellular ROS sensing and metabolism are firmly regulated by a variety of proteins involved in the redox mechanism. In this review, PTEN and the roles of oxidative stress in phosphoinositide-3 kinase/AKT signaling are summarized with a focus on the links between the pathways and ROS in cancer and aging.