Sodium/proton (Na+/H+) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis1. In humans, their dysfunction has been linked to diseases, such as, hypertension, heart failure and epilepsy and they are well-established drug targets2. The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli1,3, where both EM and crystal structures are available4-6. NhaA is made up of two distinct domains, a Core domain and a Dimerisation domain. In the NhaA crystal structure a cavity is located between the two domains providing access to the ion-binding site from the inward-facing surface of the protein1,4. Like many Na+/H+ antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, where a conformational change is thought to occur7. To date, the only reported NhaA crystal structure is of the low pH inactivated form4. Here, we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus at 3 Å resolution, solved from crystals grown at pH 7.8. In the NapA structure, the Core and Dimerisation domains are in different positions to those seen in NhaA and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to directly coordinate ion-binding1,8,9, a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the Core domain, some 20° against the Dimerisation interface. We conclude that despite their fast transport rates of up to 1500 ions/sec3, Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general.