Blundell's research interests lie in elucidating the architecture and function of macromolecules and their multi-component assemblies using methods from biochemistry, protein crystallography, and bioinformatics, with the objectives of understanding biological function, of knowledge-based prediction of structure, and of discovering new therapeutics for cancer and tuberculosis. Systems studied include DNA repair, hormones, growth factors and hormone/receptor interactions, cellular signalling, crystallins (lens proteins), renin and HIV protease. He has contributed 235 crystal structures to the worldwide Protein Data Bank (accessed 3/3/16). At least seven of the Molecule-of-the-Month features at the RCSB site of the worldwide Protein Databank have featured molecular structures solved and studied by the Blundell lab, such as the glucagon hormone shown at left in David Goodsell's drawing, nerve growth factor, the RAD51-BRCA2 DNA recombination complex, and the DNA ligase shown at right. His group has written several broadly used bioinformatics programs. He co-authored a textbook on protein crystallography with Louise Johnson, which was translated into French and Russian.