A three-dimensional model of the human dopamine transporter was constructed by molecular modeling techniques from its amino acid sequence, based on sequence analysis of this and 9 other transporter proteins. The model has 12 membrane spanning alpha-helices arranged in two 7-helical bundles, loops between helices and amino- and carboxy termini. The molecular electrostatic potentials were mainly negative at the synaptic side and positive in the cytoplasmic domains of the transporter model, strongly positive in some of the transmembrane domains, and strongly negative in other transmembrane domains. The model suggests specific binding sites for dopamine and cocaine, a functional role for chloride ions, and accounts for known structure-activity relationships of cocaine analogs at the dopamine transporter.