Accumulation of oxidative stress is considered to be a causative mediator of kidney disease, and oxidative stress can affect some key regulators of kidney homeostasis and control a number of signaling pathways that are relevant to kidney disease. The p66Shc adaptor protein was discovered more than two decades ago as a pivotal regulator of oxidative stress. Given the importance of oxidative stress in kidney homeostasis, several molecular and cellular studies using a p66Shc antagonist have depicted a role for p66Shc in renal pathophysiology. The specificity of p66Shc functions may depend upon their intracellular localization and expression in the kidney. This review focuses on the biochemical functions of the p66Shc adaptor protein, as well as its potential implications in the pathophysiology of kidney disease. In addition, the concept that pharmacologic modulation of p66Shc expression and activity may serve as a novel and effective target for the treatment of kidney disease is discussed.