Rheumatic fever (RF) and rheumatic heart disease (RHD) are post-infectious complications of an infection (or repeated infection) with the Gram-positive bacterium Streptococcus pyogenes (also known as group A streptococcus, GAS). RF and RHD are global problems and affect many indigenous populations of developed countries and many developing countries. However, RF and RHD are only part of a larger spectrum of diseases caused by this organism. The development of a vaccine against GAS has primarily targeted the abundant cell-surface protein called the M-protein. This review focuses on different M-protein-based-subunit vaccine approaches and the different delivery technologies used to administer these vaccine candidates in preclinical studies.