AbstractThe double‐stranded RNA‐dependent kinase PKR has been described for many years as strictly a pro‐apoptotic kinase. Recent data suggest that the main purpose of this kinase is damage control and repair following stress and, if all else fails, apoptosis. Aberrant activation of PKR has been reported in numerous neurodegenerative diseases and cancer. Although a subset of myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia contain low levels of PKR expression and activity, elevated PKR activity and/or expression have been detected in a wide range of hematologic malignancies, from bone marrow failure disorders to acute leukemia. With the recent findings that cancers containing elevated PKR activity are highly sensitive to PKR inhibition, we explore the role of PKR in hematologic malignancies, signal transduction pathways affected by PKR, and how PKR may contribute to leukemic transformation. J. Cell. Physiol. 223:572–591, 2010. © 2010 Wiley‐Liss, Inc.