Viruses are dependent on the cellular translation machinery for protein synthesis. Part of the innate immune response to infection is activation of the stress kinase PKR which phosphorylates the alpha subunit of the initiation factor eIF2. This results in inhibition of translation and is intended to block virus replication. A downstream effect of translational shutoff involves the formation of cytoplasmic granules, termed stress granules (SGs), that contain mRNAs, initiation factors, ribosomal subunits, and other mRNA regulatory proteins. SGs hold mRNAs in a translationally inactive state until cells recover from stress. Recent studies have begun to elucidate the impact of SGs on virus replication. Not surprisingly, viruses from diverse families have been found to modulate SG formation in infected cells by associating with important SG effecter proteins. This review describes the current knowledge on SGs and their interaction with and impact on virus replication.