We describe the development of the Cross- Ontological Analytics (XOA) system, which implements a novel web-enabled approach for computing similarities across gene and gene products with associated specifications of functional genomic relationships. The XOA system enables biologists to leverage combinations of hierarchical and associative data across multiple subontologies in order to reveal relationships between gene and gene products that might not otherwise be exposed by existing methods of computational analysis. We also provide examples of specific proof-ofconcept applications in which XOA has been successfully tested.