Impaired intracellular Ca2+ handling in atrial fibrillation (AF) has attracted much scientific interest because of its relation to AF-associated contractile dysfunction and proarrhythmic mechanisms. However, less attention has been paid to the role of Na+ despite the fact that cellular Ca2+ and Na+ concentrations are closely interlinked via the Na+,Ca2+ exchanger (NCX). Na+ enters cardiomyocytes via voltage-dependent Na+ channels or Na+,Ca2+ exchanger (NCX). Here we wish to scrutinize AF-induced alterations in atrial Na+ influx and discuss their potential as targets for pharmacologic interventions. In chronic atrial fibrillation, peak Na+ currents are about 20% smaller than in SR, but other electrophysiological parameters and sensitivity of Na+ channels to blockers (flecainide, vernakalant) are similar. It has recently been reported that human atrial cardiomyocytes from patients in AF develop a “late” Na+ current (INa,late) that is selectively suppressed by the antianginal drug ranolazine at concentrations that do not affect peak INa. In search of evidence for INa,late we studied atrial action potentials (APs) with low and high concentrations of ranolazine (30 µM versus 300 µM). SR and AF preparations exhibited the typical spike-and-dome versus triangular AP configuration, respectively. Low concentrations of ranolazine did not significantly alter AP shapes, whereas 300 µM markedly suppressed the upstroke, and prolonged APD90. In voltage clamp experiments with 100 ms-long test pulses from -110 mV to +20 mV followed by a 100 ms repolarising ramp pulse we could not detect any INa,late that was clearly distinguishable from leak currents. As a positive control, robust INa,late could be induced with Anemonia sulcata toxin ATX II (30 nM to 1 µM). NCX activity is up-regulated in AF, giving rise to an increased risk of delayed afterdepolarization and to enhanced Ca2+ removal from the cells possibly contributing to contractile dysfunction. Indeed, block of NCX with the selective compound SEA0400 produced a positive inotropic effect in rat atrial and ventricular myocardium. However, in SR and AF atrial trabeculae SEA0400 failed to increase force of contraction or alter the shape of the cardiac action potential. Interestingly, in isolated cardiomyocytes, NCX activated by elevation of extracellular Ca2+ concentration from 0 to 1 mM in the presence of extra- and intracellular Na+ concentrations of 0 and 100mM, respectively, was markedly blocked by SEA0400. Our findings in human atrial preparations suggest that further research is necessary before INa,late and NCX can be accepted as potentially useful drug targets in AF.