The kidney consists of numerous cell types organized into the nephron, which is the basic functional unit of the kidney. Any stimuli that induce loss of these cells can induce kidney damage and renal failure. The cause of renal failure can be intrinsic or extrinsic. Extrinsic causes include cardiovascular disease, obesity, diabetes, sepsis, and lung and liver failure. Intrinsic causes include glomerular nephritis, polycystic kidney disease, renal fibrosis, tubular cell death, and stones. The kidney plays a prominent role in mediating the toxicity of numerous drugs, environmental pollutants and natural substances. Drugs known to be nephrotoxic include several cancer therapeutics, drugs of abuse, antibiotics, and radiocontrast agents. Environmental pollutants known to target the kidney include cadmium, mercury, arsenic, lead, trichloroethylene, bromate, brominated-flame retardants, diglycolic acid, and ethylene glycol. Natural nephrotoxicants include aristolochic acids and mycotoxins such as ochratoxin, fumonisin B1, and citrinin. There are several common characteristics between mechanisms of renal failure induced by nephrotoxicants and extrinsic causes. This common ground exists primarily due to similarities in the molecular mechanisms mediating renal cell death. This review summarizes the current state of the field of nephrotoxicity. It emphasizes integrating our understanding of nephrotoxicity with pathological-induced renal failure. Such approaches are needed to address major questions in the field, which include the diagnosis, prognosis and treatment of both acute and chronic renal failure, and the progression of acute kidney injury to chronic kidney disease.