We have analysed the contribution of the Msn2/4 transcription factors and the Ras-cAMP-protein kinase A (PKA) pathway to the control of the yeast H2O2 response. Strains deleted for MSN2 and MSN4 are hypersensitive to H2O2, although they can still adapt to this oxidant. They are also unable to induce 27 proteins of the H2O2 stimulon as shown by quantitative two-dimensional gel analysis. This peculiar H2O2 tolerance defect, the nature of the proteins of the Msn2/4 regulon, and the partial overlap of this regulon with the Yap1 H2O2-response regulon, suggest an independent and distinctive role of these two H2O2 stress response pathways. A strain lacking PDE2, and therefore carrying high intracellular cAMP levels, is also hypersensitive to H2O2. In the presence of exogenous cAMP, this strain does not induce the entire H2O2 Msn2/4 regulon and some other proteins. This, and the normal H2O2 induction of a gene reporter under control of the Yap1 regulator when intracellular cAMP level are high, demonstrate that the Ras-cAMP pathway negatively affects the H2O2 stress response through Msn2/4. However, the high H2O2 sensitivity of a strain lacking the PKA-negative regulatory subunit Bcy1, is not only the consequence of the inhibition of Msn2/4 but also of Yap1 through a yet undefined mechanism.