With the growing commodification of advanced instrumentation capabilities, there is a need for further expansion of alternative spectral libraries. Whereas most LC-MS/MS spectral libraries use collision-induced dissociation (CID) or higher-energy C-trap dissociation (HCD), various other fragmentation techniques, such as electron-induced dissociation (X. , ultraviolet photodissociation , charge transfer dissociation (W. D. , and others , can now be used as well. Because different fragmentation techniques can result in dramatically different MS/MS fragmentation patterns, traditional spectral libraries might not be suitable for MS/MS spectral matching of such data and custom libraries will be needed. Even when using CID/HCD fragmentation, different instrument platforms or employing different collision energies can produce MS/MS data that exhibit dissimilar fragmentation behavior. Consequently, it is not always possible to get a spectral match when data is collected differently. Nevertheless, we recommend searching experimental MS/MS data against the broadest possible relevant spectral libraries, irrespective of instrument platform details. Even if the MS/MS spectra differ to some extent, it can still be possible to obtain relevant matches, especially with modern algorithmic techniques that preprocess spectra to try to minimize the effects of experimental variability. Furthermore, some advanced MS/MS fragmentation strategies might enable synergies between previously disparate library generation efforts. For example, CID spectra can contain a non-negligible number of radical fragment ions (K. , and fragmentation mechanisms from electron-induced dissociation techniques show significant similarity to fragmentation events under electron ionization, which is commonly used in gas chromatography mass spectrometry (GC-MS) . This suggests that it could be possible to repurpose the information content from large amounts of historical spectral libraries that have been generated for GC-MS.