Abstract Background The Midwest Center for Structural Genomics (MCSG) is one of the large-scale centres of the Protein Structure Initiative (PSI). During the first two phases of the PSI the MCSG has solved over a thousand protein structures. A criticism of structural genomics is that target selection strategies mean that some structures are solved without having a known function and thus are of little biomedical significance. Structures of unknown function have stimulated the development of methods for function prediction from structure. Results We show that the MCSG has met the stated goals of the PSI and use online resources and readily available function prediction methods to provide functional annotations for more than 90% of the MCSG structures. The structure-to-function prediction method ProFunc provides likely functions for many of the MCSG structures that cannot be annotated by sequence-based methods. Conclusions Although the focus of the PSI was structural coverage, many of the structures solved by the MCSG can also be associated with functional classes and biological roles of possible biomedical value.