Protein post-translational modifications (PTM) are widespread in eukaryotic cells and have a significant influence on the structure and function of proteins. The rapid development of tandem mass spectrometry (MS/MS) has provided a sensitive and accurate platform in high throughput PTM identification. However, the traditional database search engines could not meet the needs of modification data analysis, which has made the unrestricted modification search become one of the major methods/strategies to identify modifications in proteomics. Without requirement to specify the type of modifications in advance, unrestricted modification search can detect a large number of known and unanticipated modifications from the samples, which is of great significance to improve the identification rate of tandem mass spectra and reveal the biological function of proteins. In this paper, we first described the definition and development of unrestricted modification search. Then we discussed the algorithms of unrestricted PTM identification based on two major approaches, sequence matching and spectral matching，as well as the quality control of modification identification. Finally, we summarized several applications of unrestricted PTM identification, and the challenges and strategies discussed here could benefit the future research.