Advances in genomics and proteomics require new tools in molecular biology. In our laboratory, we are developing synthetic organic and inorganic molecules as structural probes of DNA and proteins. Through molecular engineering, we synthesize the compounds to recognize and bind to specific DNA sequences or protein residues. To date, we have used naphthalimide derivatives that are readily synthesized and functionalized. Upon activation with UV or visible light, the compounds initiate a sequence of chemical events that lead to cleavage of the macromolecule at the binding site. In parallel, transient laser spectroscopy is used to understand reaction mechanisms. Once the fragments are identified using HPLC and mass spectrometry, the DNA or protein structure may be reconstructed. Thus, these ‘photonucleases’ and ‘photoproteases’ provide new tools to identify the sequence and 3D structure of DNA and proteins.