High-volume hemofiltration is an extracorporeal therapy that has been available in the intensive care unit for more than 10 yr. Recent improvements in technology have made its clinical application easier and safer. However, the definition, indications, and management of this technique are still unclear, and considerable controversy and confusion remain. The aim of this review is to analyze the available data while taking into account the distinction between two very different clinical situations: acute kidney injury requiring renal support, and severe inflammatory states where blood purification has been suggested as an adjuvant therapy. For patients with acute kidney injury requiring renal replacement therapy, the two largest multicenter studies performed to date established that high ultrafiltration flow rates are not necessary. Conversely, much experimental and some clinical evidence suggest that high-volume hemofiltration can be beneficial for the subset of critically ill patients with severe inflammatory states such as septic shock.