Despite major advances in pharmacological therapy and cardiac devices, heart failure patients continue to be frequently (re-)hospitalized with signs and symptoms of fluid overload. Diuretics improve the symptoms of fluid overload, but their effectiveness is reduced by a number of factors including excess salt intake, underlying chronic kidney disease, renal adaptation to their actions and neurohormonal activation. Ultrafiltration (UF) is a mechanical method of fluid removal with several potential advantages over diuretic-based conventional therapies: several recent studies have demonstrated favorable clinical response to UF therapy. Such studies have shown that removal of large amounts of isotonic fluid, in addition to relieving symptoms of congestion, can improve exercise capacity, reduce cardiac filling pressures, restore diuretic responsiveness, and portend a favorable effect on cardio-pulmonary, cardiorenal interactions, and neurohormonal hyperactivation. However, despite these proposed benefits, so far, no clinical study has yet been carried out to explore the impact of UF therapy on hard clinical endpoints such as long-term mortality. In this article, we review a number of mechanistic aspects of UF therapy, with particular emphasis on cardio-pulmonary and cardiorenal interactions, and revisit the results of more recent clinical trials in order to highlight the characteristics that can help identify patients who are more likely to benefit from this therapeutic modality.