Ion beams have been used for a number of years in material analysis. SIMS has been used recently to study the interaction of adsorbed gases on metal surfaces and the molecular structure of organic, inorganic, biologic, and polymeric compounds. This paper reviews the advancing field of molecular SIMS applied in two distinct areas: as an analytical tool for surface analysis and as a sensitive ionization source for nonvolatile and thermally-labile molecules. The present understanding of the molecular ion formation process is illustrated by results of calculation and experiment. Comparison of SIMS with other new ionization methodologies in mass spectrometry such as field, plasma, and laser desorption shows clear spectral similarities. In addition, SIMS demonstrates an extreme surface sensitivity, best detection limits in the picogram range, and high mass capability (≳5000 amu). Ionization of nonvolatile and thermally labile molecules can occur via three separate processes involving cationization/anionization, electron transfer, or direct sputter emission of positive and negative secondary ions. Over 80 papers are referenced.