The functions of nucleotides and nucleic acids involve their interactions with cellular proteins.  In this presentation, I will discuss about our recent efforts toward the development and applications of quantitative proteomic methods for unbiased, proteome-wide discovery of proteins that can recognize unique secondary structures of DNA. I will also discuss our recent development of targeted quantitative proteomic methods for interrogating ATP- and GTP-binding proteins at the entire proteome scale. The application of these methods for uncovering novel targets of clinically used kinase inhibitors and for revealing novel drivers and suppressors for melanoma metastasis will also be presented. Through this presentation, I hope to illustrate that quantitative proteomics constitutes a power tool for discovering novel nucleic acid- and nucleotide-binding proteins and for revealing their functions in cells.