Structural heterogeneity remains one of the most significant factors complicating (and in some extreme cases making impossible) electrospray ionization mass spectrometry (ESI MS)-based analysis in a variety of fields ranging from personalized medicine to industrial-scale production of recombinant proteins, including extensively glycosylated proteins, antibody-drug conjugates, gene therapy products, and heparin-derived medicines. The broad mass distribution leads to a significant overlap of ionic signals representing different charge states, resulting in a continuum spectrum with no distinguishable features that can be used to determine the ionic charge and calculate the mass. To address these problems, novel mass spectrometry-based approaches are developed that incorporate with gas-phase ion/ion reactions to expand the capabilities of ESI MS in the field of structurally heterogeneous macromolecules and their assemblies. The list includes SRAS-CoV-2 spike protein and its complexes with the host cell receptor, immunogenic complexes formed by heparin and platelet factor 4 in the development of viii heparin-induced thrombocytopenia disorder, large complexes formed by antibodies cross-linked by bivalent antigens, and haptoglobin and its complexes with hemoglobin.