It has recently been shown that protein structures can be determined from nuclear magnetic resonance (NMR) chemical shifts using a molecular fragment replacement strategy. In these approaches, structural motifs are selected from existing protein structures on the basis of chemical shift and sequence homology and assembled to generate new structures. Here, we demonstrate that it is also possible to determine structures of proteins by directly incorporating experimental NMR chemical shifts as structural restraints in conformational searches, without the use of structural homology and molecular fragment replacement. In this approach, a protein is folded from an extended conformation to its native state using a simulated annealing procedure that minimizes an energy function that combines a standard force field with a term that penalizes the differences between experimental and calculated chemical shifts. We provide an initial demonstration of this procedure by determining the structure of two small proteins, with alpha and beta folds, respectively.