Complexation between a ligand molecule and a nucleic acid leads to optical changes that can be used to monitor the binding process. As these host—drug interactions frequently involve a reversible mechanism, a determination of the equilibrium binding constant can provide insight into the nature and strength of the underlying intermolecular events. Analysis of the induced spectral effects can also reveal considerable detail about the host-drug stoichiometry, binding site size, and the thermodynamics of complex formation. Extension of these techniques to defined-sequence oligonucleotides can highlight possible site- or sequence-specific binding, a key factor in the rational design of drugs for potential use in gene-targeted chemotherapy. Successful studies have been reported for both RNA and DNA systems, including condensed triple- and four-stranded systems. The present discussion, restricted to examples involving duplex DNA, illustrates the general principles involved in these powerful optical techniques.