When interpreting spectrum annotations from spectral library searching, it is essential to have a clear understanding of the information that mass spectrometry can and cannot provide . For example, mass spectrometry may not always distinguish between isomeric molecules. Although the Metabolomics Standards Initiative provides guidelines to denote the level of identification rigor for reported metabolite identifications , these do not fully capture the ambiguity related to isomers (e.g. using an ontology) and do not provide a system to build provenance into the confidence of spectrum annotations. Additionally, MS/MS spectra might not contain sufficiently discriminative information to annotate specific molecules if there are too few fragment ions or no unique fragment ions. Analyzing non-discriminative MS/MS spectra is equivalent to searching a genetic sequence database with a two-mer oligonucleotide, which would result in an excessive number of non-specific matches. Instead, when few ions are available or the sample contains multiple isomers, spectral library annotations might only go up to the molecular family if fragment ions correspond to similar (sub)structures that are shared by related molecules. Therefore, it is recommended that users do not restrict themselves to only the top MS/MS match obtained using spectral library searching, but carefully consider lower ranked MS/MS matches that fall within the user defined inclusion criteria of acceptable errors of MS and MS/MS ions, and minimum number of matching fragment ions. If there are multiple annotations with similar MS/MS match scores that correspond to isomeric molecules or belong to the same molecular family-which usually consists of isomeric structures-additional information is needed to further refine the most likely candidate structures. At present, verifying such ambiguity often still involves careful manual investigation by expert users, isolation and NMR confirmation, or purchase or synthesis of all possible structures to validate the assignments. In the future, we anticipate that a new generation of computational mass spectrometry tools that can directly communicate this information to the user will be developed, for example by rolling up spectrum annotations to the family level or indicating spectral evidence of the (sub)structures that can be unambiguously explained. The goal of these tools should be to clearly communicate the maximum amount of knowledge that can be derived from the mass spectral data and then follow up with additional experiments to differentiate among all possible annotations.