252Cf Plasma desorption (PD), matrix-assisted laser desorption (MA-LDI) and electrospray ionization (ESI) time-of-flight (TOF) mass spectrometric techniques were invented few decades ago and have been used extensively to analyze large non-volatile bio-molecules by desorbing/ ionizing them into the gaseous phase. However, since the introduction of these techniques, the ion formation and matrix effects have been under constant debate. This monograph which is the outgrowth of my doctoral dissertation, describes ionization pathways and matrix-effects in PD-, LDI-TOF MS considering low- mass natural products below 1.0 kDa. The probable explosive matrix-assistance in PD-TOF-MS, via the explosive energy flow through explosive decomposition under the action of 252Cf fission fragment impact is also described. Furthermore, the potential of ESI Fourier transform ion cyclotron resonance MS coupled with MS/MS to characterize the individual components present in a mixture is demonstrated. This work also describes the construction details and preliminary results of the first MALDI-TOF mass spectrometer in Sri Lanka.