SEQUEST , quickly became the de facto standard in the field, facilitated by the development of dozens of search engines (reviewed in ). Despite the popularity of database search for assigning peptides to MS2 spectra, the development of de novo sequencing continued in parallel, primarily because database searching does not work well in some application domains. By definition, a database search can only correctly assign peptides to native spectra, i.e., MS2 spectra for which the generating peptide is present in the database . Foreign spectra, whose generating peptides are not in the database, cannot be correctly identified through this method. In the analysis of a typical human sample-or indeed, any organism with a well-characterized genome-most observed MS2 spectra are assumed to be native, with only a small fraction representing unexpected contaminants or peptides harboring genetic variants. On the other hand, in metaproteomics, where peptides are extracted from, e.g., environmental samples or a gut microbiome, constructing a relevant peptide database is challenging . Even with a database derived from DNA sequencing of the same sample, many foreign spectra will remain. Other settings that require de novo sequencing include immunopeptidomics , antibody sequencing , and paleoproteomics ; the first two due to the vast search space of possible native peptides and the latter due to the presence of foreign spectra.