Circular dichroism (CD) is a useful technique for an assessment of DNA-binding mode, being a more accessible, low-resolution complement to NMR and X-ray diffraction methods. Ligand-DNA interactions can be studied by virtue of the interpretation of induced ligand CD signals resulting from the coupling of electric transition moments of the ligand and DNA bases within the asymmetric DNA environment. This protocol outlines methods to determine the binding mode and affinity of ligand-DNA interactions and takes approximately 7.5 h.