Oxidants, including hydrogen peroxide (H2O2), have been recognized for years to mimic insulin action on glucose transport in adipose cells. Early studies also demonstrated the complementary finding that H2O2 was elaborated during treatment of cells with insulin, suggesting that cellular H2O2 generation was integral to insulin signaling. Recently, reactive oxygen species elicited by various hormones and growth factors have been shown to affect signal transduction pathways in various cell types. We recently reported that insulin-stimulated H2O2 modulates proximal and distal insulin signaling, at least in part through the oxidative inhibition of protein tyrosine phosphatases (PTPases) that negatively regulate the insulin action pathway. Nox4, a homologue in the family of NADPH oxidase catalytic subunits, was found to be prominently expressed in insulin-sensitive cells. By various molecular approaches, Nox4 was shown to mediate insulin-stimulated H2O2 generation and impact the insulin signaling cascade. Overexpression of Nox4 also significantly reversed the inhibition of insulin-stimulated receptor tyrosine phosphorylation by PTP1B, a widely expressed PTPase implicated in the negative regulation of insulin signaling, by inhibiting its catalytic activity. These recent studies have provided insight into Nox4 as a novel molecular link between insulin-stimulated reactive oxygen species and mechanisms involved in their modulation of insulin signal transduction.