p66Shc is the only known proapoptotic member of the Shc protein family of molecular adaptors. Through its redox activity, p66Shc oxidates cytochrome-c, leading to increased ROS production and, eventually, to apoptosis. p66Shc has been implicated in the control of oxidative stress and life span in mammals. In this review the multifaceted role of p66Shc in redox regulation will be discussed, with a focus on the mechanisms underlying p66Shc-dependent apoptosis and its role in oxidative stress-related diseases.