Group A streptococci (GAS) are responsible for numerous human illnesses, ranging from pharyngitis to severe invasive infections, such as necrotizing fascitis and toxic shock syndrome to the postinfectious sequelae, acute rheumatic fever (ARF), and glomerulonephritis. To date, to develop a vaccine, studies have focused on the M protein. However, designing a vaccine to prevent GAS infection based on this molecule has been hampered by the vast number of M protein serotypes and the possibility that it may induce potentially harmful autoimmune reactions. In this article, the authors discuss recent approaches to overcoming the problems of an M proteinbased vaccine. In addition, recent studies identifying the protective properties of other streptococcal antigens and their potential as vaccine candidates are discussed.