Proteins of the interleukin-6 (IL-6) family bind to receptors in the plasma membrane. Subsequent signal transduction involves activation of the janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins. STAT proteins are translocated into the nucleus, where they bind to the promoter region of target genes and are thereby involved in regulating the transcription of target genes. In the first part, the present review focusses on the role of STAT3 in ischemia/reperfusion injury and in cardioprotection by ischemic pre- and postconditioning. In the heart, ischemia induces an increase in IL-6 cytokines, which is associated with activation of STAT3. Genetic modification of the myocardial STAT3 protein content shows a protective role of STAT3 on infarct size after ischemia/reperfusion injury. The cardioprotection by both early and late ischemic preconditioning as well as by ischemic postconditioning involves an activation of STAT3 and is dependent on STAT3 protein level. Whereas the infarct-sparing effect of late preconditioning is clearly mediated by an increase in transcription-mediated protein synthesis, early preconditioning is independent of gene transcription, suggesting a role of STAT3 independent of transcriptional regulation. Possibly, STAT3 plays a role in modifying mitochondrial function, organelles central for the cardioprotection by pre- and postconditioning. In the second part, the role of STAT3 in physiological stresses such as aging and pregnancy, as well as in pathophysiological situations such as myocardial infarction and heart failure is summarized. Furthermore, the requirements for the use of STAT3 as a target for treatment strategies of cardiovascular diseases is discussed.