Zare is well known for his research in laser chemistry, particularly the development of laser-induced fluorescence, which he has used to study reaction dynamics and analytical detection methods.  His research on the spectroscopy of chemical compounds suggested a new mechanism for energy transference in inelastic collisions.
He and his students have developed tools and  techniques to examine chemical reactions at the molecular and nanoscale levels. They have explored a wide-ranging variety of problems in physical chemistry and chemical analysis including examination of heterogeneous structures in mineral samples, the contents of cells and subcellular compartments, and the chemical analysis of liquid samples.
Early in his career, the question of whether laser-induced fluorescence (LIF) could be used to study aflatoxins spurred Zare to adapt LIF for use on liquids.  Work with postdoc Gerald Diebold resulted in the first use of LIF for detection in chemical analysis. 
This opened up the potential for a wide variety of fluid applications, including the detection of single molecules in liquids at room-temperature and detection methods for capillary electrophoresis.
Zare and his coworkers have combined CCD imaging with LIF detection to detect amol and zeptamole amounts of FITC-labelled amino acids.
Zare and his students have also developed cavity ring-down spectroscopy (CRDS) for quantitative diagnosis, and for high performance liquid chromatography (HPLC)  
Zare is also involved in the development of desorption electrospray ionization (DESI) techniques, which are being used for mass spectrometric imaging of lipids, metabolites and proteins in tissue samples, including prostate cancer.
Zare has also worked with NASA and others on astrobiology. He is one of the co-authors of a paper that appeared in Science in 1996, raising the possibility that a meteorite from Mars, ALH84001, contained traces of Martian life. Zare used  two-step laser mass spectrometry (L2MS), a technique that is particularly sensitive to organic molecules, to examine samples from the interior of the meteorite. He found that the  4.5-billion-year-old Martian meteorite, discovered in Antarctica, contained polycyclic aromatic hydrocarbons. This lead researchers to speculate on the presence of fossilized remains from Mars. Other researchers questioned this interpretation, suggesting that the sample might have been contaminated after its arrival on Earth. Considerable controversy resulted, which Zare felt disrupted his ongoing laboratory research. Zare has also worked with NASA on examinations of organic materials obtained from Comet 81P/Wild by the Stardust Spacecraft.