Despite progress in antimicrobial therapy, septicemia remains a major problem of modern medicine. The clinical features and outcome may vary in different clinical settings and in a single setting during the years. As an example, gram-negative bacilli have been the prevalent cause of fulminant septicemia in granulocytopenic patients during the seventies. Nowdays, the use of indwelling central venous catheters and/or quinolone prophylaxis have favored the emergence of coagulase-negative staphylococci as a major cause of septicemia in these patients. As a consequence, the optimal management of febrile episodes in granulocytopenic patients should include not only a combination of a broad spectrum betalactam plus an aminoglycoside to prevent early death from gram-negative septicemia, but also antistaphylococcal antibiotics in cases not improving after 72 hours. The clinical spectrum of infective endocarditis continues to evolve. Infection of the right heart valves that was rare until a few decades ago, is now a frequent cause of staphylococcal septicemia in intravenous drug addicts. Along with prosthetic valve infection, new clinical syndromes of nosocomial endocarditis are emerging. Infections of permanent central venous catheters, ventriculoatrial shunts or pace-maker leads may in fact cause right-sided infective endocarditis. Septicemia will continue to challenge physicians in the future.