The development of edematous states is usually due to heart failure, renal failure, hepatic failure, or a combination of these conditions. Although the number of patients with edema and ascites due to hepatic cirrhosis or renal failure is less frequent than with congestive heart failure, the treatment of these conditions is often difficult. Although diuretic therapy is often employed, effective reduction in edema or ascites may be difficult to achieve and is associated with significant side effects including hyponatremia, hypotension, and a further decrease in renal function. Aggressive diuretic therapy of ascites may result in hepatic encephalopathy or hepatorenal syndrome. Each condition needs to be evaluated, and an optimum therapeutic approach needs to be devised. This article provides a review of the challenges and therapeutic approaches for the treatment of these conditions and provides a review of new therapies on the horizon that may be promising.