The FXYD proteins are a family of seven homologous single transmembrane segment proteins (FXYD1-7), expressed in a tissue-specific fashion. The FXYD proteins modulate the function of Na,K-ATPase, thus adapting kinetic properties of active Na+ and K+ transport to the specific needs of different cells. Six FXYD proteins are known to interact with Na,K-ATPase and affect its kinetic properties in specific ways. Although effects of FXYD proteins on parameters such as K(1/2)Na+, K(1/2)K+, K(m)ATP, and V(max) are modest, usually twofold, these effects may have important long-term consequences for homeostasis of cation balance. In this review we summarize basic features of FXYD proteins and present recent evidence for functional effects, structure-function relations and structural interactions with Na,K-ATPase. We then discuss possible physiological roles, based on in vitro observations and newly available knockout mice models. Finally, we also consider evidence that FXYD proteins affect functioning of other ion transport systems.