Over the last two decades, the known functions of the mineralocorticoid receptor (MR) have expanded beyond regulation of sodium and potassium in epithelial cells to encompass physiological and pathophysiological effects in many tissues throughout the body. It is now well accepted that the MR plays a critical role in many aspects of cardiovascular disease. Areas covered: Recent studies employing tissue-selective MR null mice have added valuable insights into the cellular mechanisms that translate MR activation into cardiac remodeling and dysfunction. Together with earlier pharmacological studies using MR antagonists the apparent protective effects of tissue-selective MR deletion support the observed clinical benefits of MR antagonists in heart failure. Given the potential risk of side effects of current therapies, a key goal is the identification of tissue-selective MR antagonists that will provide cardiovascular protection, but spare renal function. As such, the specific cellular mechanisms regulated by MR located in the cardiovascular system may provide the basis for the development of targeted therapies. Expert opinion: This review will address the function of the MR, and its regulation of the cellular mechanisms that determine cell-specific MR signaling in cardiovascular disease and briefly discuss the potential for novel therapeutic targets that will allow for cardiac selective MR blockade.