Disordered states of proteins include the biologically functional intrinsically disordered proteins and the unfolded states of normally folded proteins. In recent years, ensemble-modeling strategies using various experimental measurements as restraints have emerged as powerful means for structurally characterizing disordered states. However, these methods are still in their infancy compared with the structural determination of folded proteins. Here, we have addressed several issues important to ensemble modeling using our ENSEMBLE methodology. First, we assessed how calculating ensembles containing different numbers of conformers affects their structural properties. We find that larger ensembles have very similar properties to smaller ensembles fit to the same experimental restraints, thus allowing a considerable speed improvement in our calculations. In addition, we analyzed the contributions of different experimental restraints to the structural properties of calculated ensembles, enabling us to make recommendations about the experimental measurements that should be made for optimal ensemble modeling. The effects of different restraints, most significantly from chemical shifts, paramagnetic relaxation enhancements and small-angle X-ray scattering, but also from other data, underscore the importance of utilizing multiple sources of experimental data. Finally, we validate our ENSEMBLE methodology using both cross-validation and synthetic experimental restraints calculated from simulated ensembles. Our results suggest that secondary structure and molecular size distribution can generally be modeled very accurately, whereas the accuracy of calculated tertiary structure is dependent on the number of distance restraints used. Proteins 2011. © 2011 Wiley Periodicals, Inc.