The ability of bacteria to sense and respond to both environmental and intracellular metal concentrations plays an important role in pathogenesis. The acquisition of manganese is vital for the virulence of several bacterial species. Although manganese uptake systems have been well studied in bacteria, no manganese efflux system has yet been identified. In this study we have identified a cation diffusion facilitator (CDF) protein (Sp1552) of unknown substrate specificity that functions as a manganese export system in Streptococcus pneumoniae. We designated the gene for this manganese efflux system mntE and found that the mutant strain was highly sensitive to manganese stress. Although the mutant was more resistant to oxidative stress and produced more H(2)O(2) and pili, it had reduced virulence in a murine model of infection, indicating that manganese export plays a role in host pathogenesis. There was a distinct differential transcriptional response to extracellular and intracellular manganese accumulation. Our study indicates that manganese efflux is required for invasive disease and may provide a useful antimicrobial target to devise future therapeutics.