In plants, we have invented new technology to design mutants of the photosynthetic enzyme Rubisco with improved catalytic efficiency and substrate specificity (validated experimentally in a model plant). Rubisco is almost solely responsible for fixing CO2 into the energy-rich compounds of life. Our approach combined our computational insights on the enzyme’s mechanism with phylogenetic analyses developed from readily available structural and sequence data, allowing us to make precise predictions of multiple residues to mutate. In essence, we have invented a procedure for reduction of sequence space; that is we identify the subset of the protein’s residues it is useful to mutate, what they should be mutated to, and how multiple mutations should be grouped. We are developing our method for re-engineering more efficient Rubiscos into crop plants for greater productivity and specific features such as drought tolerance. Other potential applications are biomass and biofuel production, and carbon sequestration.