Phosphorylation of the Ser-139 residue of the histone variant H2AX, forming γH2AX, is an early cellular response to the induction of DNA double-strand breaks. Detection of this phosphorylation event has emerged as a highly specific and sensitive molecular marker for monitoring DNA damage initiation and resolution. Further, analysis of γH2AX foci has numerous other applications including, but not limited to, cancer and aging research. Quantitation of γH2AX foci has also been applied as a useful tool for the evaluation of the efficacy of various developmental drugs, particularly, radiation modifying compounds. This review focuses on the current status of γH2AX as a marker of DNA damage and repair in the context of ionizing radiation. Although the emphasis is on γ-radiation-induced γH2AX foci, the effects of other genotoxic insults including exposure to ultraviolet rays, oxidative stress and chemical agents are also discussed.