When a MALDI MS sample on a substrate is irradiated with a pulse of laser, photons are absorbed by matrix molecules. The excited matrix molecules relax to ground state rapidly and converts the photo energy to thermal energy, which heats up the sample. According to an estimation based on delivered lase energy, the upper limit of plume temperature could reach as high as 2,700 K. The matrix is usually more volatile than the analytes. Rapid evaporation of the matrix molecules brings the less volatile or non-volatile analyte molecules into the gas phase. The thermal desorption may also involve ejection of clusters into the plume. It is generally accepted in the literature that direct cation formation by ejection of electrons from matrix molecules is unlikely due to the need of three or more photons for the process to be energetically feasible. For example, the energy of the photon of the commonly used 337 nm nitrogen laser in MALDI MS is 3.68 eV, while the commonly used matrices have an ionization energy of ~8 eV or higher. Various models have been proposed to address the problem. Examples include multiphoton ionization, exciton pooling, excited state proton transfer, ground state autoprotolysis, preformed ion emission, and reduction of charged clusters into individual ions. Among them, the preformed ion emission model is simple and intuitive. Upon laser irradiation, matrix and analyte ions are ejected into the gas phase along with neutral matrix and analyte molecules. The ion pair thermal model considers preformed ions ejected into the gas phase as one of the ion sources.