A review is given from the stand-point of applying methods utilizing electrospray ionization – mass spectrometry (ESI-MS) for quantitative binding (affinity and selectivity) determinations in small molecule host-guest (receptorligand, selector-selectand, etc.) systems. Advantages over more commonly utilized and traditional solution phase approaches, both in the context of developing new chiral selector molecules for separation and purification of enantiomers and in drug discovery applications, are presented. Although the majority of studies employing methods such as host-guest screening, competitive binding, and titrations have focused on large protein-ligand, DNA-ligand, and RNA-ligand systems, the use of ESI-MS for studying small molecule and chiral recognition systems is growing. For the latter case, greater care must be given to considering the effects of the ESI process on the ionization of the species involved in equilibria of interest. Some basic mechanistic and practical concerns for performing solution-phase-targeting quantitative measurements by ESI-MS are given in this light. Finally, an account of the application of these methods in a high throughput format is given, highlighting the potential of traditional and novel screening and titration approaches which allow scientists to screen the performance of hundreds, if not thousands, of compounds in a single day.