Transporter proteins are specific to their respective transmitter. In the case of serotonin, a transporter protein found in the plasma membrane of serotonergic neurons is responsible for re-uptake of the transmitter. The transporter protein acts as a carrier of serotonin molecules across the membrane. Unlike channels which stay open or closed, transporters undergo conformational changes (changes in their three dimensional shape) and move one molecule in each cycle.

The serotonin transporter (SERT) is similar to other biogenic amine transporters (e.g. norepinephrine and dopamine transporters) and is part of a family of sodium (Na+) and chloride (Cl-) dependent transporters. The transporter gene has been cloned from rat brain, human brain, and human placenta. While there have been different species of mRNA found for the gene, all SERTs seem to have come from a common gene. SERTs, with molecular weights of 60-80 kDA, have twelve transmembrane domains (TM) with a large extracellular loop between TMs 3 and 4. Both the N- and C-termini are located within the cytoplasm. There are six potential sites of phosphorylation by protein kinase A and protein kinase C, and regulation of SERTs by protein kinases has been reported. The large extracellular loop and the intracellular parts of the N- and C-termini do not appear to be the significant sites that determine interactions with 5-HT or transporter inhibitors. Rather, the areas important for selective 5-HT affinity appear to be localized within TMs 1-3 and TMs 8-12. It is believed that SERTs have a common binding site for 5HT and many of its inhibitors.

SERT activity, like serotonin, is seen most often in the raphe nuclear complex. SERTs have also been seen in the amygdala, thalamus, hypothalamus, substantia nigra, and locus coeruleus. In addition to being found on neurons, SERTs are seen in the placenta, lungs, and blood platelets. Blood platelets utilize SERTs to obtain serotonin from the environment because they cannot synthesize it themselves. In the placenta, SERTs may protect heavily vascularized embryonic tissue from constricting too early due to maternal serotonin.