Cancer cells are characterized by a peculiar pH condition, being the extracellular compartment acidic and the intracellular one neutral or basic, i.e. the opposite of what happens in normal cells. The reversal of the pH contributes to cancer cell proliferation and drug resistance. Among the different enzymes regulating pH gradient, proton transporters Na+/H+ exchangers (NHEs) are considered as suitable targets for drugs that ultimately counteract cancer cell survival. This review will describe the properties of NHEs, focusing on the prototype NHE1 and on the effect of its inhibition on cancer cell metabolism.