Group A Streptococcus (GAS) is a Gram-positive bacterium associated with a variety of mucosal and invasive human infections. GAS systemic disease reflects the diverse abilities of this pathogen to avoid eradication by phagocytic defenses of the innate immune system. Here we review how GAS can avoid phagocyte engagement, inhibit complement and antibody functions required for opsonization, impair phagocytotic uptake mechanisms, promote phagocyte lysis or apoptosis, and resist specific effectors of phagocyte killing such as antimicrobial peptides and reactive oxygen species. Understanding the molecular basis of GAS phagocyte resistance may reveal novel therapeutic targets for treatment and prevention of invasive human infections.