Structure-based drug design tries to mutually map pharmacological space populated by putative target proteins onto chemical space comprising possible small molecule drug candidates. Both spaces are connected where proteins and ligands recognize each other: in the binding pockets. Therefore, it is highly relevant to study the properties of the space composed by all possible binding cavities. In the present contribution, a global mapping of protein cavity space is presented by extracting consensus cavities from individual members of protein families and clustering them in terms of their shape and exposed physicochemical properties. Discovered similarities indicate common binding epitopes in binding pockets independent of any possibly given similarity in sequence and fold space. Unexpected links between remote targets indicate possible cross-reactivity of ligands and suggest putative side effects. The global clustering of cavity space is compared to a similar clustering of sequence and fold space and compared to chemical ligand space spanned by the chemical properties of small molecules found in binding pockets of crystalline complexes. The overall similarity architecture of sequence, fold, and cavity space differs significantly. Similarities in cavity space can be mapped best to similarities in ligand binding space indicating possible cross-reactivities. Most cross-reactivities affect co-factor and other endogenous ligand binding sites. Proteins 2009. © 2008 Wiley-Liss, Inc.