DNA is the target biomolecule of many anticancer drugs because DNA replication is one of the most vulnerable cellular process. The mode of action of these drugs may occur in the electronic ground state, as in platinum-based complexes employed in chemotherapy, or in electronically excited states, as in photosensitizers employed in photodynamic therapy. The simulation of both types of DNA damage is very challenging since it requires an accurate quantum mechanical description of the reactive region of the system while including the biological environment in the theoretical model. Advanced theoretical methods currently employed to simulate DNA damage will be discussed together with several applications.