Raman crystallography refers to the use of a Raman microscope to follow chemical changes in single crystals of macromolecules. Thus, the consequences of ligand binding to enzyme active sites and (slow) chemical reactions can be probed. Beta-lactamases are are a major target for anti-bacterial drug therapy but unfortunately the enzymes develop resistance to drug binding, often by undergoing single amino acid replacements within the protein. The present study sets out to define the molecular mechanism of drug resistance by comparing the reactions of commonly used drugs in crystals of wild-type beta-lactamase with crystals containing a point mutation found in drug resitant isolates from the clinic. The drugs are the mechanism-based (suicide) inhibitors, tazobactam, sulbactam and clavulanic acid. The reactions are carried out in crystals because this medium provides very high quality Raman data and because the Raman studies complement and guide X-ray crystallographic analysis. Thus, the Raman data identify the optimal time for flash freezing crystals for X-ray analysis in order to trap targetted intermediates on the reaction pathway.