The ability of opportunistic pathogens such as Group A Streptococcus (GAS) to transition between mucosal colonisation and invasive disease requires complex systems for adapting to markedly different host environments. The battle to acquire essential trace metals such as manganese and iron from the host is central to pathogenesis. Using a molecular genetic approach, Turner et al. [Biochem. J. (2019) 476, 595–611] show that it is not just individual metal concentrations that are important, but the ratio of iron to manganese within cells. Increasing this ratio by knocking out pmtA, encoding the Fe(II) exporter PmtA, or by disrupting mtsA, encoding an MtsABC Mn(II)-import system component, led to reductions in superoxide dismutase (SodA) activity and increased sensitivity to oxidative stress. The authors show that SodA is at least 4-fold more active with Mn bound than with Fe and speculate that high intracellular Fe:Mn ratios reduce superoxide dismutase activity through the mismetalation of SodA. Challenging wild-type GAS with 1 mM H2O2 led to a decrease in Fe:Mn ratio and a 3-fold increase in SodA activity, indicating that modulation of the balance between intracellular Fe and Mn may play an important role in adaptation to oxidative stress. This work unravels some of the key mechanisms for maintaining appropriate Mn and Fe concentrations within bacterial cells and underscores the need for future studies that take an holistic view to metal ion homeostasis in bacteria. Strategies aimed at interfering with the balance of intracellular metal ions represent a promising approach for the control of invasive microbial infections.