The innate immune system employs a variety of antimicrobial oxidants to control and kill host-associated bacteria. Hypothiocyanite/hypothiocyanous acid (OSCN/HOSCN) is one such antimicrobial oxidant that is synthesized by lactoperoxidase, myeloperoxidase, and eosinophil peroxidase at sites throughout the human body. HOSCN has potent antibacterial activity while being largely non-toxic towards human cells. The molecular mechanisms by which bacteria sense and defend themselves against HOSCN have only recently begun to be elaborated, notably by the discovery of bacterial HOSCN reductase (RclA), an HOSCNdegrading enzyme widely conserved among bacteria that live on epithelial surfaces. In this paper, I show that Ni sensitizes to HOSCN by inhibiting glutathione reductase, and that inorganic polyphosphate protects against this effect, probably by chelating Ni ions. I also found that RclA is very sensitive to inhibition by Cu and Zn, metals that are accumulated to high levels by innate immune cells, and that, surprisingly, thioredoxin and thioredoxin reductase are not involved in HOSCN stress resistance in . These results advance our understanding of the contribution of different oxidative stress response and redox buffering pathways to HOSCN resistance in and illustrate important interactions between metal ions and the enzymes bacteria use to defend themselves against oxidative stress.