The pericardium is a unique structure that surrounds the heart and serves several important physiological roles. The removal of the pericardium, certain pericardial disorders, or the buildup of fluids within this space will ultimately alter hemodynamic performance. Recent therapeutic approaches have been directed to exploit the space that exists between the pericardium and the epicardial surface of the heart. New devices and techniques are being developed to access this space with minimally invasive approaches. The pharmacokinetics of many drugs may be greatly enhanced if the drug is delivered into the pericardium. As more is learned about the pericardium, it may play a significant role in cardiac therapies.