Diuretic resistance is defined as a failure to achieve the therapeutically desired reduction in edema despite a full dose of diuretic. The causes of diuretic resistance include poor adherence to drug therapy or dietary sodium restriction, pharmacokinetic issues, and compensatory increases in sodium reabsorption in nephron sites that are not blocked by the diuretic. To illustrate the pathophysiology and management of diuretic resistance, we describe a patient with nephrotic syndrome. This patient presented with generalized pitting edema and weight gain despite the use of oral loop diuretics. Nephrotic syndrome may cause mucosal edema of the intestine, limiting the absorption of diuretics. In addition, the patient's kidney function had deteriorated, impairing the tubular secretion of diuretics. He was admitted for intravenous loop diuretic treatment. However, this was ineffective, likely due to compensatory sodium reabsorption by other tubular segments. The combination of loop diuretics with triamterene, a blocker of the epithelial sodium channel, effectively reduced body weight and edema. Recent data suggest that plasmin in nephrotic urine can activate the epithelial sodium channel, potentially contributing to the diuretic resistance in this patient. This case is used to illustrate and review the mechanisms of, and possible interventions for, diuretic resistance.