The Conserved Domain Architecture Retrieval Tool (CDART) performs similarity searches of the NCBI Entrez Protein Database based on domain architecture, defined as the sequential order of conserved domains in proteins. The algorithm finds protein similarities across significant evolutionary distances using sensitive protein domain profiles rather than by direct sequence similarity. Proteins similar to a query protein are grouped and scored by architecture. Relying on domain profiles allows CDART to be fast, and, because it relies on annotated functional domains, informative. Domain profiles are derived from several collections of domain definitions that include functional annotation. Searches can be further refined by taxonomy and by selecting domains of interest. CDART is available at http://www.ncbi.nlm.nih.gov/Structure/lexington/lexington.cgi.