Management of pneumococcal infections has been challenged by the development of resistance and, more recently, the unexpected spread of resistant clones of serotypes, such as 19A, following the introduction of a conjugate pneumococcal vaccine for use in children in 2000. High-dose penicillin G and many other agents continue to be efficacious parenterally for pneumonia and bacteremia. However, treatment options for meningitis and for infections treated with oral agents, particularly in children, have been limited by resistance. Empiric treatment guidelines should reflect the emerging threats from increased drug resistance. Compliance with guidelines by physicians and patients is important to prevent further development of resistance as new classes of agents are unlikely to be available in the next decade.