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Organometallic ruthenium(II)-arene complexes are currently attracting increasing interest as anticancer compounds with the potential to overcome drawbacks of traditional drugs like cisplatin with respect to resistance, selectivity, and toxicity. Rational design of new potential pharmaceutical compounds requires a detailed understanding of structure–property relationships at an atomic level. We performed in vacuo density functional theory(DFT) calculations, classical MD, and mixed QM/MM Car-Parrinello MD explicit solvent simulations to rationalize the binding mode of two series of anticancer ruthenium(II) arene complexes to double-stranded DNA (dsDNA).Binding energies between the metal centers and the surrounding ligands as well as proton affinities were calculated using DFT. Our results support a pH-dependent mechanism for the activity of the RAPTA [Ru(?6-arene)X2(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) compounds. Adducts of the bifunctional RAPTA and themonofunctional [Ru(?6-p-cymene)Xen]+ series of compounds with the DNA sequence d(CCTCTG*G*TCTCC)/d(GGAGACCAGAGG), where G* are guanosine bases that bind to the ruthenium compounds through their N(7) atom, have been investigated. The resulting binding sites were characterized in QM/MM molecular dynamics simulations showing that DNA can easily adapt to accommodate the ruthenium compounds.