As top-down mass spectrometry methods continue to advance, new data interpretation methods to identify fragment ions in MS/MS spectra are crucial. Identification of fragment ions directly in the m/z domain is being readily incorporated into several software methods, including TDValidator and ExDViewer and now Proteo-SAFARI, enabling more direct assessment of MS/MS data without the need for prior deconvolution. Additionally, Proteo-SAFARI facilitates direct estimation of the contributions of various hydrogen-shifted fragment ions to the net isotopic distribution of an observed fragment, enabling more specific evaluation of the types of fragments generated by UVPD. This SAFARI approach has already been extended to top-down analysis of nucleic acids, and development of platforms for annotation of MS/MS data for other classes of biomolecules is underway.