Nickel is the cofactor of the Helicobacter pylori urease enzyme, a factor essential for the chronic colonization of the acidic hostile environment in the human stomach. The NikR regulatory protein directly controls urease expression and regulates the uptake of nickel, and is also able to regulate the expression of other regulatory proteins including the iron-responsive regulator Fur. Through regulatory crosstalk and overlapping regulons, the NikR protein controls the expression of many systems important for colonization and acid adaptation. Despite the paucity of regulatory proteins, this enables H. pylori to optimally adapt to conditions in the stomach, making it one of the most successful human pathogens.