The thermodynamics of ligand–protein binding has recently gained increased attention due to the recognition that enthalpy and entropy changes accompanying binding can carry significant information on the quality of interactions. In the context of drug discovery, the thermodynamic quantities of binding have been suggested to be related to the drug-like properties of ligands and ultimately to the developability of drug candidates.1,2 The thermodynamic profile of ligand binding, i.e. the enthalpic and entropic contributions to the binding free energy, reflects the structural features and the interactions of the ligand and the protein. However, a detailed understanding of how structural changes affect thermodynamic profiles is still missing. It appears that the complex process of ligand binding which includes conformational changes, desolvation and formation of new interactions between the ligand and the protein gives various and, to a large extent, compensating contributions to both enthalpy and entropy. Nevertheless, it has been recognized that enthalpic contributions are often dominated by optimal polar interactions while entropic contributions come at a large extent from the desolvation that releases water molecules from the solvation shell and allows them to join bulk water. These trends manifest themselves in the ligand size dependence of thermodynamic profiles, that is, smaller ligands tend to bind with favourable enthalpy while favourable entropy changes become increasingly important in the binding of larger ligands.3 Since fragments usually bind in the high micromolar to the low millimolar range and endothermic binding for small molecule–protein interactions is relatively rare, (around 20% for all interactions in the SCORPIO and BINDING databases), the enthalpy gain of fragment binding is not unexpected. In the current contribution, however, we show that – in contrast to drug-like molecules – the contribution of favourable fragment binding enthalpy tends to dominate over entropic terms. We analyse this trend by investigating the theoretical background and experimental data of the binding of small compounds. We focus our analyses on fragment-sized compounds whose heavy atom number does not exceed 22. It is worth mentioning that fragments have emerged as a key tool in drug discovery as they provide highly suitable chemical starting points for medicinal chemistry optimizations. In the forthcoming analysis, we show that in contrast to other opinions which are more ambivalent about the enthalpic signature of fragments4,5 they do have some particular features that lead to specific thermodynamic profiles and this discriminates them from larger compounds.