Streptococcus pyogenes (group A streptococcus) colonises skin and throat tissues resulting in a range of benign and serious human diseases. Opsonisation and phagocytosis are important defence mechanisms employed by the host to destroy group A streptococci. Antisera against the cell-surface M protein, of which over 150 different types have been identified, are opsonic and contribute to disease protection . In this issue of Molecular Microbiology, Sandin and colleagues have comprehensively analysed the regions of M5 protein that contribute to phagocytosis resistance and opsonisation. Human plasma proteins bound to M5 protein B- and C-repeats were shown to block opsonisation, an observation that needs to be carefully considered for the development of M protein-derived vaccines. Whilst safe and efficacious human group A streptococcal vaccines are not commercially available, candidate M protein-derived vaccines have shown promise in murine vaccine models and a recent phase 1 human clinical trial.