Mammalian cells respond to interferons (IFNs) secreted during infection by the transcriptional upregulation of as many as a thousand genes. This remarkable transition prepares cells and organisms for resistance to infection, and many IFN-regulated gene products are players in well-understood resistance programs. Oddly, however, many of the most abundantly induced proteins are GTPases whose functions are not well understood. Here we review the progress that has been made toward understanding the roles of individual GTPase families in disease resistance and the hints of common mechanisms that are now available.