The protein kinase R (PKR) is an intracellular sensor of stress, exemplified by viral infection. Double-stranded (ds) RNA produced during viral replication activates PKR, which in turn arrests protein synthesis by phosphorylating the alpha subunit of the translation initiation factor eIF2. As well as dsRNA, two additional ligands, PACT and heparin, directly activate the kinase. These mediate the response of PKR to additional indirect stimuli, including bacterial lipopolysaccharides, ceramide and polyanionic molecules. This responsiveness to multiple stimuli advocates a broader role for PKR as a signalling molecule for diverse physiological stresses. Appropriately, a number of other protein substrates have been reported for PKR. These substrates support additional roles for PKR in the regulation of transcription and signal transduction in infected cells, as well as uninfected but diseased tissues, such as in tumorigenesis and neurodegenerative diseases. Finally, PKR plays a role in normal cell differentiation in platelet-derived growth factor signalling and in osteoblast-mediated calcification.