Acute kidney injury (AKI) is a common and serious postoperative complication following exposure to cardiopulmonary bypass (CPB). Several mechanisms have been proposed by which the kidney can be damaged and interventional studies addressing known targets of renal injury have been undertaken in an attempt to prevent or attenuate CPB-associated AKI. However, no definitive strategy appears to protect a broad heterogeneous population of cardiac surgery patients from CPB-associated AKI. Although the association between hemoglobinuria and the development of AKI was recognized many years ago, this idea has not been sufficiently acknowledged in past and current clinical research in the context of cardiac surgery-related AKI. Hemoglobin-induced renal injury may be a major contributor to CPB-associated AKI. Accordingly, we now describe in detail the mechanisms by which hemoglobinuria may induce renal injury and raise the question as to whether CPB-associated AKI may actually be, in a significant part, a form of pigment nephropathy where hemoglobin is the pigment responsible for renal injury. If CPB-associated AKI is a pigment nephropathy, alkalinization of urine with sodium bicarbonate might protect from: (1) tubular cast formation from met-hemoglobin; (2) proximal tubular cell necrosis by reduced endocytotic hemoglobin uptake, and (3) free iron-mediated radical oxygen species production and related injury. Sodium bicarbonate is safe, simple to administer and inexpensive. If part of AKI after CPB is truly secondary to hemoglobin-induced pigment nephropathy, prophylactic sodium bicarbonate infusion might help attenuate it. A trial of such treatment might be a reasonable future investigation in higher risk patients receiving CPB.