It is quite well established that activation of the AT(2) receptor (AT(2)R) provides a counter-regulatory role to AT(1)R overactivity, particularly during pathological conditions. Indeed, a potential therapeutic role for the AT(2)R is currently being promulgated with the introduction of novel AT(2)R ligands such as compound 21 (C21). In this brief review, we will focus on recent evidence to suggest that AT(2)R exhibits promising organ protection in the context of the heart, kidney and brain, with inflammation and gender influencing outcome. However, this field is not without controversy since the 'flagship' ligand C21 has also come under scrutiny, although it is safe to say there is much evidence to support a potentially important role of AT(2)R in a number of cardiovascular diseases. This report updates recent data in this field.