Understanding the thermodynamic and binding characteristics of DNA minor groove binders (MGBs) is important for the rational design and development of novel MGBs; however, there are contradicting results in the literature regarding the thermodynamic signature of MGBs. The expansion of the thermodynamic database for MGBs in the literature was encouraging to evaluate and critically test the previously reported hypothesis that MGB binding is mainly entropically driven. In this review, the thermodynamic data of a group of MGBs published in the literature were analyzed to better understand the factors that drive minor groove recognition. Analysis of the enthalpic and entropic contributions to the free energy of binding for 20 interactions from a total of 14 different compounds reveals that MGB binding can be driven by enthalpy, entropy, or by both and that is mainly dictated by ligand structural heterogeneity. These findings could be useful in the design of MGBs for therapeutic purposes.