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The Protein Structure Initiative (PSI) was established in 2000 by the National Institutes of General Medical Sciences with the long-term goal of providing 3D (three-dimensional) structural information for most proteins in nature. As advances in genomic sequencing, bioinformatics, homology modelling, and methods for rapid determination of 3D structures of proteins by X-ray crystallography and nuclear magnetic resonance (NMR) converged, it was proposed that our understanding of the biology of protein structure and evolution could be greatly enabled by 'genomic-scale' protein structure determination. Over the past 12 years, the PSI has evolved from a testing bed for new methods of sample and structure production to a core component of a wide range of biology programs.