The concentrative power of the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) is thought to be fueled by the transmembrane Na + gradient, but it is conceivable that they can also tap other energy sources, for example, membrane voltage and/or the transmembrane K + gradient. We have addressed this by recording uptake of endogenous substrates or the fluorescent substrate APP + (4-(4-dimethylamino)phenyl-1-methylpyridinium) under voltage control in cells expressing DAT, NET, or SERT. We have shown that DAT and NET differ from SERT in intracellular handling of K + . In DAT and NET, substrate uptake was voltage-dependent due to the transient nature of intracellular K + binding, which precluded K + antiport. SERT, however, antiports K + and achieves voltage-independent transport. Thus, there is a trade-off between maintaining constant uptake and harvesting membrane potential for concentrative power, which we conclude to occur due to subtle differences in the kinetics of co-substrate ion binding in closely related transporters.