The Na-K/H-K-ATPase gene family is divided in three subgroups including the Na-K-ATPases, mainly involved in whole body and cellular ion homeostasis, the gastric H-K-ATPase involved in gastric fluid acidification, and the newly described nongastric H-K-ATPases for which the identification of physiological roles is still in its infancy. The first member of this last subfamily was first identified in 1992, rapidly followed by the molecular cloning of several other members. The relationship between each member remains unclear. The functional properties of these H-K-ATPases have been studied after their ex vivo expression in various functional expression systems, including the Xenopus laevisoocyte, the insect Sf9 cell line, and the human HEK 293 cells. All these H-K-ATPase α-subunits appear to encode H-K-ATPases when exogenously expressed in such expression systems. Recent data suggest that these H-K-ATPases could also transport Na+in exchange for K+, revealing a complex cation transport selectivity. Moreover, they display a unique pharmacological profile compared with the canonical Na-K-ATPases or the gastric H-K-ATPase. In addition to their molecular and functional characterizations, a major goal is to correlate the molecular expression of these cloned H-K-ATPases with the native K-ATPases activities described in vivo. This appears to be more complex than anticipated. The discrepancies between the functional data obtained by exogenous expression of the nongastric H-K-ATPases and the physiological data obtained in native organs could have several explanations as discussed in the present review. Extensive studies will be required in the future to better understand the physiological role of these H-K-ATPases, especially in disease processes including ionic or acid-base disorders.