While certain residues have clear involvement in determining the 3D structure of a macromolecule because they affect the folding topology or the overall protein stability, the role of different residues in ligand accommodation and binding has attracted less attention. On the basis of the assumption that drug-binding sites on target molecules have specific amino acid compositions, the incidence of each standard amino acid at the binding sites of small molecules and their correlations are calculated for an unprecedented large set of high-quality X-ray structures. Results show, for the first time, strong and highly correlated enrichments of aromatic and sulfur-containing residues, which play an important role in ligand binding and shape the nature of the chemical interactions.