Histone's H2A variant (H2AX) phosphorylation is an early indicator of DNA double-strand breaks formation and DNA damage response. Thus, it may act as a novel biomarker to monitor genotoxic events that can drive cancer development and tumor progression. This review will focus on the possible applications of H2AX as a key regulator of DNA damage response in lung cancer and as a biomarker of: sensitivity of lung tumors to chemotherapy and radiotherapy, treatment with PARP inhibitors, bystander effect, multistep lung carcinogenesis, environmental smoking, and chemical genotoxicity, chemoprevention, prognosis, and also as therapeutic targets in lung cancers.