AbstractQuantifying the properties of macromolecules is a prerequisite for understanding their roles in biochemical processes. One of the less‐explored geometric features of macromolecules is molecular surface irregularity, or ‘roughness’, which can be measured in terms of fractal dimension (D). In this study, we demonstrate that surface roughness correlates with ligand binding potential. We quantified the surface roughnesses of biological macromolecules in a large‐scale survey that revealed D values between 2.0 and 2.4. The results of our study imply that surface patches involved in molecular interactions, such as ligand‐binding pockets and protein‐protein interfaces, exhibit greater local fluctuations in their fractal dimensions than ‘inert’ surface areas. We expect approximately 22 % of a protein’s surface outside of the crystallographically known ligand binding sites to be ligandable. These findings provide a fresh perspective on macromolecular structure and have considerable implications for drug design as well as chemical and systems biology.