Living organisms are continually exposed to oxidants. During oxidative stress, reactions of oxidants with biological macromolecules can result in both direct damage and the formation of long-lived, reactive, hydroperoxides. The series of studies undertaken in this work focused on the early cellular events following generation of reactive singlet oxygen (1O2) and identified that long-lived protein hydroperoxides, a major product of protein oxidation, can play a significant role in cellular damage by selectively targeting both low-molecular mass and protein thiols. These findings are invaluable in providing an insight of the early molecular events of oxidative stress and a cornerstone for future research in developing a better strategy to prevent oxidative damage.