Pyelonephritis is often considered a benign disease, yet in some studies as high as 35 percent of the cases progressed to severe renal disease. Treatment failures occur because of relapse of infection, emergence of secondary infecting organisms, re-infection and the development of antibiotic resistance. In addition, inadequate renal tissue concentrations of antibiotics account for a majority of treatment failures. The factors which influence diffusion of antibiotics into renal tissues are discussed. The importance of renal medullary tissue levels of antibiotics is emphasized, as well as the influence that protein binding, non-ionic diffusion and the state of hydration have on these levels. Distribution kinetics of sulfisoxazole, ampicillin, tetracyclines, cephalosporins, nalidixic acid, nitrofurantoin, gentamicin, carbenicillin indanyl sodium, sulfamethoxazole and trimethoprim as they relate to the treatment of pyelonephritis are also presented.