Among antimicrobial agents that have consistently been efficacious in treating infections due to specific bacteria over extended periods of time, there are few better examples than Streptococcus pneumoniae and penicillin. Until recently in the United States (U.S.), this combination had remained nearly uniformly effective. The sole issue mitigating for or against use of penicillin (or ampicillin) in the management of systemic pneumococcal infections, or oral ampicillin (or amoxicillin) in treating localized, nonlife-threatening pneumococcal infections, was the penicillin allergy status of the patient. In the nonallergic patient, penicillin or its congeners, have been the drugs of choice largely because resistance to these agents remained uncommon. All of that changed dramatically in the U.S. during the early part of the decade of the 1990s with the emergence of high rates of antimicrobial resistance with S. pneumoniae, and concomitantly, the recognition of diminished efficacy when certain other antimicrobials were used to treat pneumococcal infections. The intent of this discussion is to address a variety of specific issues that pertain to the problem of antimicrobial resistance with S. pneumoniae. The format chosen is a selection of the most asked questions regarding S. pneumoniae and antimicrobial resistance, and then answers are provided.