Serotonin reuptake transporters (SERTs) are dependent on extracellular Na+ and extracellular Cl-. Unlike Na+, Cl- can be at least partly substituted for by NO2-, Br-, and other anions. Intracellular potassium (K+) is also used in the process but can be replaced by other ions, most notably hydrogen (H+). The driving force for the energetically unfavorable transport of serotonin is the Na+ influx down its concentration gradient. The Na+/K+ pump (Na+/K+ ATPase) maintains the extracellular Na+ concentration as well as the intracellular K+ concentration. Na+/K+ ATPase pumps three Na+ ions our for each two K+ ions pumped into the cell. The electrical potential produced, in addition to creating the Na+ concentration used by the transporter protein, also leads to the loss of Cl- ions from the cell which are also used in transport.

According to the present model of SERT function, the first step occurs when Na+ binds to the carrier protein. Serotonin, in its protonated form (5HT+), then binds to the transporter followed by Cl-. Chloride ions are not required for 5HT+ binding to occur but are necessary for net transport to take place. The initial complex of serotonin, Na+, and Cl- creates a conformational change in the transporter protein. The protein, which began by facing the outside of the neuron, moves to an inward position where the neurotransmitter and ions are released into the cytoplasm of the neuron. Intracellular K+ then binds to the SERT to promote reorientation of the carrier for another transport cycle. The unoccupied binding site becomes, once again, exposed to the outside of the cell and the K+ is released outside the cell.