Oxidants such as H₂O₂ are connected to lymphocyte activation, but the molecular mechanisms behind this phenomenon are less clear. Here, I review data suggesting that by inhibiting protein tyrosine phosphatases, H₂O₂ plays an important role as a secondary messenger in the initiation and amplification of signaling at the antigen receptor. These findings explain why exposure of lymphocytes to H₂O₂ can mimic the effect of antigen. In addition, more recent data show that antigen receptors themselves are H₂O₂-generating enzymes and that the oxidative burst in macrophages seems to play a role not only in pathogen killing but also in the activation of these as well as neighboring cells. Thus, by controlling the activity of the negative regulatory phosphatases inside the cell, H₂O₂ can set and influence critical thresholds for lymphocyte activation.