Cardiotrophin (CT)-1 was discovered by coupling expression cloning with an embryonic stem cell-based model of cardiogenesis. Comparison of similarity in amino acid sequence and conformational structure indicates that CT-1 is a member of the interleukin (IL)-6 type cytokine family that shares the transmembrane signaling protein, glycoprotein (gp) 130 as a receptor. These cytokines mediate overlapping pleiotropic actions on a variety of cell types including cardiac myocytes, hepatocytes, megakaryocytes, osteoclasts, and neuronal cells. CT-lmediates its hypertrophic and cytoprotective properties through the Janus kinase/signal transducers and activators of transcription (JAK/STAT), mitogen-activated protein (MAP) kinase, phosphatidylinositol (PI) 3 kinase, and nuclear factor kappa B (NFkappaB) pathways. CT-1 gene and protein are distributed not only in the heart, but also in the pulmonary, renal, gastrointestinal, cerebral, and muscular tissues. CT-1 could also be synthesized and secreted from vascular endothelial cells and adipocytes. CT-1 has hypertrophic actions on the cardiac myocytes, skeletal muscle cells, and smooth muscle cells as well as cytoprotective actions on the cardiac myocytes, neuronal cells, and hepatocytes. CT-1 is circulating in the body, and its plasma concentration is increased in various cardiovascular and renal diseases such as hypertension, congestive heart failure, myocardial infarction, valvular heart disease, metabolic syndrome, and chronic kidney disease. Treatment with CT-1 is beneficial in experimental animal models of cardiovascular diseases. CT-1 specifically protects the cardiac myocytes from ischemic damage when CT-1 is given not only prior to the ischemia, but also given at the time of reoxygenation. Current evidence suggests that CT-1 plays an important role in the regulation of the cardiovascular system.