Zinc plays important roles in human nutritional immunity, and in virulence of several bacterial pathogens. Zinc deficiency is also linked to increased susceptibility to bacterial infections. In this study, we investigate the role of zinc in innate immune defense against Streptococcus pyogenes (Group A Streptococcus; GAS), a human pathogen responsible for diseases ranging from pharyngitis and impetigo, to severe invasive infections. The clinically important M1T1 wild-type strain was used in this study and isogenic mutants constructed with deletions in the czcD gene (Spy0653; encodes for a putative zinc efflux pump) and adjacent gczA gene (Spy0654; encodes a putative zinc-dependent activator of czcD). Wild-type, isogenic mutants and complemented strains were tested for resistance against zinc stress, intracellular zinc accumulation and virulence. Both czcD and gczA mutants exhibited increased sensitivity to zinc. Transcriptional analyses indicate that gczA up-regulates czcD in response to zinc. Both mutants displayed increased susceptibility to human neutrophil killing and reduced virulence in a murine infection model. Furthermore, we demonstrate that neutrophils mobilize zinc in response to GAS. These data indicate that the innate immune system may use zinc as an antimicrobial agent and that, zinc efflux is an important contributor to GAS pathogenesis.