The structures and energetics, as well as several important chemical parameters, of some alkylating drug molecules in both neutral and charged states, are investigated. The reactivity of the drug molecules with the DNA bases is then determined. These studies are carried out within the framework of first-principles density functional theory (DFT), using the Becke–Lee–Yang–Parr (BLYP) generalized gradient corrections to the local spin density approximation exchange and correlation energy, norm-conserving pseudopotentials, a plane-wave expansion of Kohn–Sham orbitals, and conceptual DFT. Our results are in good agreement with the few existing experiments. Further, for most of the drug molecules studied, the Guanine moiety in DNA is found to be the primary target, validating earlier experimental findings for anti-tumour drugs.