In addition to the canonical nucleobases,nucleic acids(DNA and RNA) carry a variety of chemical modifications.More than 150 chemical modifications so far have been identified in nucleic acids.These chemical modifications do not change the sequence of nucleic acids,but may alter their structures and biochemical properties,ultimately regulating the spatiotemporal expression of genes.Uncovering the functions of these modifications could promote our understanding of the physiological regulation mechanisms of living organisms.However,the abundance of nucleic acid modifications is usually low in vivo.Therefore,highly sensitive and specific detection methods are critical to decipher the functions of nucleic acid modifications.Chemical derivatization in combination with mass spectrometry techniques demonstrate to have excellent analytical capabilities for endogenous low abundance nucleic acid modifications.In the past few years,researchers have established a variety of chemical derivatization mass spectrometry based methods for sensitive and efficient analysis of nucleic acid modifications.The recent advances in deciphering nucleic acid modifications by chemical derivatization mass spectrometry are summarized in this review,and further promotion on the future studies of nucleic acid modifications is anticipated.