The ability of Helicobacter pylori, one of the most successful human bacterial pathogens, to colonize the acidic gastric niche persistently, depends on the proper homeostasis of intracellular metal ions, needed as cofactors of essential metallo-proteins involved in acid acclimation, respiration and detoxification. This fundamental task is controlled at the transcriptional level mainly by the regulators Fur and NikR, involved in iron homeostasis and nickel response, respectively. Herein, we review the molecular mechanisms that underlie the activity of these key pleiotropic regulators. In addition, we will focus on their involvement in the transcriptional regulatory network of the bacterium, pinpointing a surprising complexity of network motifs that interconnects them and their gene targets. These motifs appear to confer versatile dynamics of metal-dependent responses by extensive horizontal connections between the regulators and feedback control of metal-cofactor availability.