Visual rhodopsins are recognized members of the large and diverse family of G protein-coupled receptors (GPCRs), but their evolutionary origin and relationships to other proteins are not known. In a previous paper [Shlykov MA, Zheng WH, Chen JS & Saier MH Jr (2012) Biochim Biophys Acta 1818, 703–717], we characterized the 4-toluene sulfonate uptake permease (TSUP) family of transmembrane proteins, and showed that these 7-transmembrane segment (TMS) or 8-TMS proteins arose by intragenic duplication of a gene encoding a 4-TMS protein, sometimes followed by loss of a terminal TMS. In this study, we show that the TSUP, GPCR and microbial rhodopsin families are related to each other and to six other currently recognized transport protein families. We designate this superfamily the transporter/opsin/G protein-coupled receptor (TOG) superfamily. Despite their 8-TMS origins, the members of most constituent families exhibit 7-TMS topologies that are well conserved, and these arose by loss of either the N-terminal TMS (more frequent) or the C-terminal TMS (less frequent), depending on the family. Phylogenetic analyses revealed familial relationships within the superfamily and protein relationships within each of the nine families. The results of the statistical analyses leading to the conclusion of homology were confirmed using hidden Markov models, Pfam and 3D superimpositions. Proteins functioning by dissimilar mechanisms (channels, primary active transporters, secondary active transporters, group translocators and receptors) are interspersed on a phylogenetic tree of the TOG superfamily, suggesting that changes in the transport and energy-coupling mechanisms occurred multiple times during evolution of this superfamily.