Structural genomics aims to solve a large number of protein structures that represent the protein space. Currently an exhaustive solution for all structures seems prohibitively expensive, so the challenge is to define a relatively small set of proteins with new, currently unknown folds. This paper presents a method that assigns each protein with a probability of having an unsolved fold. The method makes extensive use of PROTOMAP, a sequence-based classification, and SCOP, a structure-based classification. According to PROTOMAP, the protein space encodes the relationship among proteins as a graph whose vertices correspond to 13,354 clusters of proteins. A representative fold for a cluster with at least one solved protein is determined after superposition of all SCOP (release 1.37) folds onto PROTOMAP clusters. Distances within the PROTOMAP graph are computed from each representative fold to the neighboring folds. The distribution of these distances is used to create a statistical model for distances among those folds that are already known and those that have yet to be discovered. The distribution of distances for solved͞unsolved proteins is significantly different. This difference makes it possible to use Bayes' rule to derive a statistical estimate that any protein has a yet undetermined fold. Proteins that score the highest probability to represent a new fold constitute the target list for structural determination. Our predicted probabilities for unsolved proteins correlate very well with the proportion of new folds among recently solved structures (new SCOP 1.39 records) that are disjoint from our original training set. T he number of known protein sequences already exceeds 400,000 and is rapidly growing. Despite recent technological advances in structural determination (1) it is still infeasible to solve experimentally the structure of hundreds of thousands of proteins in the foreseeable future. Therefore, it is necessary to find ways to predict key structural properties of a protein based on its sequence and on data derived from structurally solved proteins. Current attempts to computationally determine a protein's structure based on sequence alone still have a limited success, partly because of the shortage in solved structures that can be used as models. The challenge, then, is to determine a relatively small set of representative proteins the solution of whose structure will enrich our known repertoire of protein folds (2). Techniques such as comparative modeling and fold recognition then will be applied for large-scale structural prediction (3). It generally is accepted that reasonable predictions are possible for proteins that share at least 30% sequence identity with some solved protein (2). The expansion and eventual completion of our archive of three-dimensional (3D) protein templates depend on the development of new methodologies to properly select an expanded (comprehensive) set of target proteins (discussed in refs. 4-8).Data accumulated from complete genomes has accelerated the development of co...