By eliciting host antimicrobial programs in nearly all nucleated cells interferons (IFNs) help orchestrate the innate immune response of mammals to a diverse array of microbial pathogens. Recent work has highlighted the complexity of this transcriptional repertoire and the emergence of several families of IFN-inducible guanosine 5' triphosphatases (GTPases)--p47, guanylate-binding protein (GBP), Mx and very large inducible GTPases (VLIG)--that subsume pathogen-specific roles. Such specificity arises from a combination of both the type and timing of inductive stimuli, target-cell population, subcellular binding partners and the infectious agent encountered. Evolution of different GTPase families to combat compartmentalized versus cytosolic pathogens reveals a hitherto unexpected level of intracellular discrimination during vertebrate host defense.