Among the many options to measure molecular interactions in solution, isothermal titration microcalorimetry (ITC) stands out as an almost universal, label‐free, operationally fast, fully computer‐operated, and thus quite robust method to acquire all thermodynamic parameters necessary to characterize the energetics of intermolecular association. Provided that there is an enthalpic response accompanying the mutual molecular interaction, the free energy, molar enthalpy, and, by using the Gibbs–Helmholtz equation, also the molar entropy can be determined in a single run. The present review describes the fundamental concept, the methodological aspects concerning the range accessible to direct determinations, and its potential expansion. Special focus is on data evaluation and the intrinsic limits to translate the macroscopic instrumental output into the illumination of the microscopic events happening on the molecular scene. The scope of ITC as a means to characterize thermodynamic equilibria is illustrated with the help from recent applications spanning from low‐molecular host–guest chemistry to multimeric assembly of surfactants observable as phase changes.