Loop diuretics are central to the management of fluid overload in acute decompensated heart failure. However, a variance in the response to loop diuretics can alter a patient’s clinical course and has an adverse effect on clinical outcomes. Thus, a diminished response to loop diuretics is an important clinical issue. Factors thought to contribute to diuretic resistance include erratic oral absorption in congested states and postdiuretic sodium retention. Further contributing to diuretic resistance in patients with advanced heart failure are decreases in renal perfusion and alterations in sodium handling that occur in an attempt to maintain circulatory homeostasis. Several pharmacologic interventions have been used to improve diuretic response. Intravenous diuretic administration, increasing diuretic doses, or changing diuretic agents can potentially overcome pharmacokinetic obstacles which contribute to drug resistance. Combination diuretic therapy may be useful to overcome increased sodium retention, dopamine may improve renal perfusion, and hypertonic saline may transiently increase intravascular volume and improve sodium delivery to the tubules of the nephron. Despite the prevalence of diuretic resistance, there remains a paucity of clinical trial evidence to help guide therapy in these patients.