Chromatin is the therapeutic target for DNA-binding medicinal agents, yet we know substantially more about the interaction of drugs with naked DNA. Current research is unraveling a dynamic gene- and transcription state-dependent structure for human chromatin and also unveiling differences in nucleosome positioning between cancer and normal cells. Considering observations on the modulation of DNA drug binding and adduct repair by histone packaging suggests potential for targeting specific sites within nucleosomes that coincide with weak points of cancer cells.