Ions produced via the charged residue mechanism have less internal energy than ions produced by ion evaporation right after droplet formation. Sources that decouple droplet formation from droplet charging, and that charge the droplets less on average, are thus also more favorable for native MS applications: the preservation of the non-covalent complexes is favored by keeping the solvent around as late as possible and by minimizing Coulomb repulsion. Future source developments aimed at maximizing large ion production from lowly charged droplets should benefit the field of structural biophysics. However, characterizing the internal energy of ions produced in conditions adequate for desolvating macro-ions will require larger thermometer ions. The GIBMS measurement of E0 values requires well-controlled single-collision conditions, achievable only on small ions. Determining their E0 values experimentally for larger ions will require new approaches, such as modeling of collisional heating and cooling combined with ion trajectory calculations . The availability of more massive computer power and new functionals will certainly help to calculate E0 values for thermometer ions with a larger number of DOFs, to calibrate instrumental conditions relevant to molecules of wider ion mobility and m/z ranges.