DNA is a molecular target for many anticancer and antiviral drugs. Therefore, a clear understanding of the interaction of small molecules with DNA is important in the rational design of ligands that can bind to DNA with high affinity and selectivity. There are several methods to investigate interactions between drug and DNA. Some of them measures changing into DNA structures, such as lengthening and untwisting of helix of DNA. Other techniques measure changing in drug environment. With the increasing availability of sensitive microcalorimeters, particular interest has arisen in the thermodynamics of drug-DNA interaction. Using such methods permit direct determination of enthalpy changes associated with reactions. One experiment permits to obtain also binding constant, hence an almost complete thermodynamic profile can be established. This profile offers key insights into the molecular forces that drive complex formation and permit to estimate which kind of interaction are responsible of forming these complexes.