We present a novel approach for the increasing reliability of compound identification for LC-MS and MALDI imaging lipidomics. Our approach is based on the characterization of compounds not only by the elution time, accurate mass, and fragmentation spectra but also by the number of labile hydrogens that can be measured using the hydrogen/deuterium (H/D) exchange approach. The number of labile hydrogens (those from -OH and -NH groups) serves as an additional structural descriptor used when performing a database search. For LC-MS experiment, the H/D exchange was performed in the heating capillary of the modified electrospray ionization (ESI) source, while for MALDI imaging, the exchange was performed in the ion funnel at 10 Torr pressure. It was observed that such an approach allowed one to achieve a considerable degree of deuteration, enough to unambiguously distinguish between different classes of lipids. The proposed analytical approach may be successfully used for the identification not only of lipids but also of peptides and metabolites. A special software for the automatic filtration of molecules based on the number of functional groups was also developed.