The penicillin family is one of the most valuable groups of antibiotics in primary care. They are bacteriocidal, well distributed, and highly efficacious against susceptible organisms. Development of synthetic penicillins has both broadened the spectrum of activity and enhanced the efficacy of these medications. However, emergence of resistant bacterial strains has limited the usefulness of penicillins in recent years. Nonetheless, penicillins remain the drugs of choice for many mild, localized soft tissue infections and are particularly important in specific situations during pregnancy. History of penicillin allergy does not necessarily prohibit the use of penicillin. In patients with a self-reported history of allergy, skin testing often fails to elicit signs of a true allergy to penicillin. Failure to prescribe penicillin for penicillin-sensitive infections in these patients contributes to the development of bacterial resistance. This paper provides a review of the modes of action, spectrums of activity, adverse effects for the various classes of penicillin most often used in primary care and highlights clinical issues in managing women with penicillin allergy.