Streptococcus pyogenes (Group A Streptococcus; GAS) is a Gram-positive human pathogen responsible for a wide spectrum of diseases. Zinc is recognized as an important metal ion in relation to nutritional immunity and zinc deficiency is linked to increased susceptibility to bacterial infection. Zinc stress impairs glucose metabolism through the inhibition of the glycolytic enzymes. In the presence of zinc, a metabolic shift to the tagatose-6-phosphate pathway allows conversion of D-galactose to dihydroxyacetone phosphate and glyceraldehyde phosphate, partially bypassing impaired glycolytic enzymes to generate pyruvate. We analyzed the clinically important GAS M1T1 wild-type strain, and the phenotypes of two isogenic mutants and corresponding complemented mutants. The targeted GAS czcD gene encodes for a putative zinc efflux pump and the adjacent gczA gene encodes a putative Zn-dependent activator of czcD expression. Compared to wild-type and complemented cells, both mutants exhibited reduced ability to grow in the presence of zinc. Transcriptional analyses indicate that gczA up-regulates czcD in response to zinc. The gczA regulator also induces galactose metabolism, circumventing zinc-induced blockage of glucose uptake. Both czcD and gczA are up-regulated in contact with human neutrophils. Zinc efflux plays a critical role in GAS pathogenesis, as both czcD and gczA mutants displayed increased susceptibility to killing by human neutrophils and reduced virulence in a murine infection model. Taken together, these results demonstrate that zinc homeostasis is an important contributor to GAS pathogenesis and innate immune defense against infection. Strategies to manipulate zinc homeostasis in order to reduce GAS infection are discussed.