Macrolide resistance (MR) in group A Streptococcus (GAS) has been well documented in several countries and has become clinically significant since the large increases in macrolide usage during the 1970s. Macrolides are recommended as an alternative therapy for GAS pharyngitis, the most common cause of bacterial pharyngitis. Macrolide resistance has been associated with certain emm types, a sequence-based typing system of the hypervariable region of the GAS M-protein gene. Clinical failure of macrolide treatment of GAS infections can be associated with complications including acute rheumatic fever and rheumatic heart disease, the leading cause of acquired heart disease in children worldwide. Here we report 2 pediatric cases of MR and/or treatment failure in the treatment of GAS pharyngitis with the subsequent development of acute rheumatic fever. We also review the literature on worldwide MR rates, molecular classifications, and emm types, primarily associated with GAS pharyngeal isolates between the years of 2000 and 2010. The use of macrolides in the management of GAS pharyngitis should be limited to patients with significant penicillin allergy.