The Center for Eukaryotic Structural Genomics (CESG) seeks to populate protein fold space through improvements in technology. To this end, we have developed a streamlined approach that employs cryogenic probes and automated analysis to more efficiently determine three-dimensional protein structures by NMR. Structures determined in our laboratory demonstrate the effectiveness of our approach for proteins produced both in cell-based E. coli expression systems as well as the cell-free wheat germ system pioneered at the CESG. Target screening by 2D NMR reveals a significant number of partly or predominantly unfolded proteins. Traditional structural biology paradigms might dismiss their functional relevance, but intrinsically unstructured proteins or regions (IUPs and IURs) are increasingly thought to derive biological activity from their dynamic properties, rather than in spite of them. IURs can impede structure determination by inhibiting crystallization, reducing solubility or obscuring NMR signals from folded domains. Removal of an IUR can be used to 'rescue' targets that would otherwise be unsuitable, but in other cases the structure of an intact protein can be solved by NMR in the presence of a dynamically disordered domain. Structural genomics and bioinformatic methods are rapidly identifying new IUPs and IURs, but most of these remain functionally uncharacterized. I will describe our efforts to determine structures of proteins containing IURs and to anticipate their biological roles. Finally, I will present an example of a dynamic signaling protein that exists not as an IUP, but rather as a reversible equilibrium between two unrelated domain folds, each with unique functional characteristics.