Several first row transition metal ions are essential micronutrients to human health and dietary deficiency has been shown to result in adverse disease outcomes. There are a number of ways in which the host immune system can use metal ion metabolism to eradicate infections; sequestration can impede bacterial growth by starvation of key metal ions while metal overload can result in poisoning of the bacterial pathogen. As a result, regulation of metal homeostasis is crucial to the virulence and survival of bacterial pathogens. Streptococcus pyogenes (Group A Streptococcus; GAS) is a Gram positive, obligate human pathogen responsible for a wide variety of disease states, ranging from pharyngitis through to necrotising fasciitis and toxic shock syndrome. GAS has two putative cation efflux proteins, CzcD and Spy0980 from the cation diffusion facilitator (CDF) family. CzcD has been shown responsible for the efflux of zinc and plays an important role in innate immune defense and virulence. Bioinformatic comparison shows that CzcD share 21% amino acid identity with Spy0980. Phylogenetic analysis of the CDF family identified a novel clade that includes Spy0980, which appears to be involved in manganese efflux. Growth of a 5448Δspy0980 mutant demonstrated increased manganese sensitivity compared to the wild-type strain 5448. Interestingly, this manganese-induced killing can be reversed with the addition of iron. To date, manganese has been considered a beneficial metal ion involved in protection against oxidative stress. However, in conjunction with manganese, the Δspy0980 mutant showed increased susceptibility to hydrogen peroxide killing. We hypothesise that increased intracellular manganese may exert its toxic effect by poisoning iron-dependent enzymes and also by stabilizing the repressor form of PerR, leading to diminished ability to respond to oxidative stress. Hence, this manganese efflux pump is predicted to be important for bacterial virulence in the host, particularly in low iron, high oxidative stress environments such as within macrophages or neutrophils.