The serotonin (5HT) transporter (SERT) is a clinically important target for serotonin selective reuptake inhibitor (SSRI) antidepressants, as well as MDMA (“ecstasy”) and cocaine. The determination of a crystal structure of the leucine transporter LeuTAa, a SERT homolog, has allowed us to model SERT in a serotonin bound state and to predict aspects of substrate selectivity and antagonist recognition. Our model predicts that specific residues associated with transmembrane domains (TMs) 1, 3, 6, and 8 comprise the 5HT (and MDMA) binding pocket. TM6 is predicted to be comprised of a set of inner and outer alpha helices connected by a flexible linker that can support TM6 reorientations during the transport cycle. Use of the substituted cysteine accessibility method (SCAM) identifies key residues in TM6 that relocate during the SERT transport cycle. Subsequent mutagenesis studies have refined our SERT models, predicting residues that govern specificity for serotonin and SSRI medications and establishing a path for the rational design of novel SERT‐targeted medications. J.R.F. is supported by NIDA 1 F31 DA023337. R.D.B is supported by NIDA Award DA07390.