The term pre-renal azotemia (or on occasion 'pre-renal renal failure') is frequently used in textbooks and in the literature to indicate an acute syndrome characterized by the presence of an increase in the blood concentration of nitrogen waste products (urea and creatinine). This syndrome is assumed to be due to loss of glomerular filtration rate but is not considered to be associated with histopathological renal injury. Thus, the term is used to differentiate 'functional' from 'structural' acute kidney injury (AKI) where structural renal injury is taken to indicate the presence of so-called acute tubular necrosis (ATN). This paradigm is well entrenched in nephrology and medicine. However, growing evidence from experimental animal models, systematic analysis of the human and experimental literature shows that this paradigm is not sustained by sufficient evidence when applied to the syndrome of septic AKI, especially in critically ill patients. In such patients, several assumptions associated with the 'pre-renal azotemia paradigm' are violated. In particular, there is no evidence that ATN is the histopathological substrate of septic AKI, there is no evidence that urine tests can discriminate 'functional' from 'structural' AKI, there is no evidence that any proposed differentiation leads or should lead to different treatments, and there is no evidence that relevant experimentation can resolve these uncertainties. Given that septic AKI of critical illness now accounts for close to 50% of cases of severe AKI in developed countries, these observations call into question the validity and usefulness of the 'pre-renal azotemia paradigm' in AKI in general.