The applications of mass spectrometry to DNA adduct and epigenetic DNA modification identification, screening, and quantitation are discussed. In mass spectrometry (MS) methodology, analyte ions are separated according to their mass to charge ratios, providing a very accurate and selective mode of detection of specific molecular species. Mass spectrometry provides valuable structural information used to unambiguously identify DNA nucleosides, nucleotides, and nucleobases. Furthermore, the use of isotope dilution mass spectrometry enables accurate, precise, and reproducible quantitation of DNA damage in tissues and cells. The field of DNA adduct analysis by mass spectrometry is expanding rapidly, as novel instrumentation and approaches are being introduced, including online sample preparation, nanoflow LC-MS, high resolution HPLC-MS/MS, and chip based methodology. Mass spectrometry based methods are widely used for sequencing of carcinogen-modified DNA and in combination with biotechnology tools, to determine the biological consequences of DNA damage.