Of the DNA bases, guanine has the smallest ionization potential (IP). The recent combined use of experimental gas-phase photoelectron data and self-consistent field (SCF) and post-SCF descriptions has provided new information about the energetics of guanine ionization at the nucleotide and dinucleotide levels (Fernando, H.; Papadantonakis, G. A.; Kim, N. S.; LeBreton, P. R. Proc. Natl. Acad. Sci. U.S.A, 1998, 95, 5550-5555. Kim, N. S.; Zhu, Q.; LeBreton, P. R. J. Am. Chem. Sec. 1999, 121, 11516-11530). The energetic matching of the highest occupied pi orbitals and the pi interaction which occurs in regions of stacked guanines (G runs) give rise to sequence-specific regions of low IF. This is described by a Koopmans analysis of results from ab initio SCF calculations with 6-31G*, 6-31G, 3-21G, and STO-3G basis sets and with ZINDO semiempirical calculations on oligonucleotides and oligonucleotide models. At the ab initio 3-21G SCF level, model calculations indicate that the lowest IP of guanine in a double-stranded G run containing three guanine-cytosine base pairs is approximately 1 eV smaller than that of free guanine. The ab initio and semiemprirical results indicate that, in double-stranded oligonucleotides containing G runs with three or four guanines, an interior guanine has the lowest IF. This occurs for oligonucleotides in both the A- and B-DNA conformations, and for oligonucleotides with strong phosphate-counterion interactions. The finding that the lowest energy base ionization occurs from the interior of G runs differs from the result reported for a model employing a double-stranded G run without sugar and phosphate groups (Saito, I.; Nakamura, T.; Nakatani, K. J. Am. Chem. Sec. 2000, 122, 3001-3006) where the guanine at the 5'-end has the lowest LP. However,it is consistent with earlier results indicating that, in G runs, the molecular electrostatic potential is more negative around guanines in the interior than around guanines at the ends. The low interior IPs correlate with guanine two-photon ionization patterns. They also correlate with the high reactivities at interior sites exhibited by the electrophilic antitumor agent bis-2-cholroethylmethylamine (nitrogen mustard) and by the potent carcinogen N-methyl-N-nitrosourea.