Viral structural genomic projects aim at unveiling the function of unknown viral proteins by employing high-throughput approaches to determine their 3D structure and to identify their function through fold-homology studies. The ‘viral enzyme module localization’ (VaZyMolO) tool has been developed, which aims at defining viral protein modules that might be expressed in a soluble and functionally active form, thereby identifying candidates for crystallization studies. VaZyMolO includes 114 complete viral genome sequences of both negative- and positive-sense, single-stranded RNA viruses available from NCBI. In VaZyMolO, a module is defined as a structural and/or functional unit. Modules were first identified by homology search and then validated by the convergence of results from sequence composition analysis, motif search, transmembrane region search and domain definitions, as found in the literature. The public interface of VaZyMolO, which is accessible from http://www.vazymolo.org, allows comparison of a query sequence to all VaZyMolO modules of known function.