Cardiotonic steroids (CTS) are a new class of hormones that circulate in the blood and are divided into two distinct groups, cardenolides, such as ouabain and digoxin, and bufadienolides, such as marinobufagenin, telocinobufagin and bufalin. They have the ability to bind and inhibit the ubiquitous transport enzyme sodium potassium pump, thus regulating intracellular Na(+) concentration in every living cell. Although digoxin has been prescribed to heart failure patients for at least 200 years, the realization that CTS are endogenously produced has intensified research into their physiological and pathophysiological roles. Over the last two decades, substantial evidence has accumulated demonstrating the effects of endogenously synthesised CTS on the kidneys, vasculature and the heart. In this review, the current state of art and the controversies surrounding the manner in which CTS mediate their pathophysiological effects are discussed. Several potential therapeutic strategies have emerged as a result of our increased understanding of the role CTS play in health and disease.