Penicillin has been the recommended drug of choice in most cases of group A streptococcus (GAS) pharyngitis for nearly 40 years based on its efficacy in the prevention of acute rheumatic fever. Since trials of other drugs for the prevention of rheumatic fever are no longer feasible in the United States, eradication of GAS pharyngitis has become the surrogate for their evaluation. On the basis of this criterion, specific therapeutic regimens have been recommended, and numerous other drugs have gained approval as alternatives to penicillin. Current therapeutic issues include possible decreased efficacy of penicillin, timing of the initiation of therapy, and drugs of choice for patients whose treatment fails, who are chronic carriers, or who have frequent infections. Criteria for assessment of new drugs include clinical response, likelihood of prevention of rheumatic fever, rates of relapse and recurrent infection, and drug safety. The establishment of uniform guidelines and definitions of response for new drug evaluations by the Infectious Diseases Society of America should aid in the further assessment of new antibacterial agents as therapy for GAS pharyngitis. However, no data yet suggest that any of these drugs should replace penicillin as the drug of choice.