Existing protein structure classifications group proteins by overall structural similarity at the highest level and by evolutionary relationships at the lowest level, deriving higher-level groups by pairwise structure comparison. For this to be successful requires that large changes in structure are relatively rare in evolution and that proteins with no detectable evolutionary relationship do not converge on similar global chain conformations since this creates conflicts between structural and evolutionary consistency. Analysis of global structural changes using core topological descriptions for 4261 domains from classes C and D of the SCOP database and new measures of topological distance and consistency of classification showed that the topological consistency of SCOP folds is highly variable with some folds having no consistent description and significant overlaps between groups including some members of separate folds with identical topological descriptions. Topological clustering shows that including sufficient indels to allow family members to be joined would also require joining several distinct folds. We conclude that evolutionary changes in the global topology of protein domains are the root cause of many difficulties for present approaches to structure classification using pairwise comparison. As a resolution we propose that a purely structural classification should be created using an approach similar to that adopted by the Gene Ontology in which proteins are assigned labels describing structure. (C) 2010 Elsevier Inc. All rights reserved.