Enzymes play prominent roles in the resistance phenotype of cells treated with ß-lactam antibiotics or with alkylating cytostatic drugs. Drug resistance is a growing problem in medicine world-wide and understanding of the molecular evolution of enzymes that inactivate drugs is important to the design of more effective drugs and to improved therapeutic regimes. Our ongoing project is primarily focused on multidrug resistance in bacteria and evolution of ß-lactamase activity inactivating antibiotics. In one mode Salmonella bacteria are subjected to alternative ß-lactam antibiotics for selection of clones expressing enzyme mutants that provide resistance. In a second and parallel mode computational studies will predict the optimal enzyme structure for inactivation of a given antibiotic. The predicted structure will be expressed from a synthetic gene. In both cases the starting point is the same designed recombinant metallo-ß-lactamase mimic. Comparison of the outcome of experimental resistance evolution in bacteria with the predicted optimal enzyme structure will reveal if alternative potent enzymes can evolve, and if the phenotype resulting from bacterial selection is only a mild version in comparison with the calculated optimal solution. GSTs offer a second system for studies relevant to anti-cancer drug resistance. In this paradigm gain of activity against alkylators and loss of sensitivity to enzyme inhibitors will be studied based on the