In January 2008, the Clinical and Laboratory Standards Institute published revised susceptibility breakpoints for penicillin and Streptococcus pneumoniae, and shortly thereafter, the United States Food and Drug Administration similarly revised its breakpoints via changes in the package insert for penicillin. The revised susceptibility breakpoint is < or =2 microg/mL for nonmeningeal infections treated with parenteral penicillin at a dosage of 12 million units-24 million units per day. The susceptibility breakpoint of < or =0.06 microg/mL remains unchanged for pneumococcal meningitis treated with parenteral penicillin at a dosage of > or =18 million units per day. Herein, we review the scientific basis for the revisions to the breakpoints, which were supported by microbiologic, pharmacokinetic and/or pharmacodynamic, and clinical data. Clinicians, once again, should feel comfortable prescribing penicillin for pneumococcal pneumonia and other pneumococcal infections outside the central nervous system.