The photosystem II (PSII) double mutant ΔPsbO:ΔPsbU was unable to grow photoautotrophically at pH 7.5, but growth was restored at pH 10. We have isolated a pseudorevertant of this strain, which exhibited photoautotrophic growth at pH 7.5. PSII-specific oxygen evolution and assembled PSII centers in the pseudorevertant and the original ΔPsbO:ΔPsbU strains were similar at pH 7.5. Comparison of global gene expression of the two strains at pH 7.5 revealed that <4% of genes differed. In the pseudorevertant, up-regulated transcripts included stress-responsive genes, many of which were shown previously to be under the control of Hik34. Elevated transcripts included those encoding heat shock proteins (HspA, DnaK2 and HtpG), two Deg proteases (DegP and DegQ), and the orange carotenoid protein (OCP, Slr1963). Up-regulated genes encoded proteins localized to different cell compartments, including the thylakoid, plasma and outer membranes. We suggest that the cell wide up-regulation of stress response genes in the pseudorevertant may limit the impact of PSII instability that is observed in the ΔPsbO:ΔPsbU strain. Futhermore, the OCP has a photoprotective role mediating phycobilisome-associated nonphotochemical quenching, such that increased OCP levels in the pseudorevertant may reduce photons reaching these impaired centers. These two responses, in combination with uncharacterized stress responses, are sufficient to permit the growth of pseudorevertant at pH 7.5.