Although enzymes catalyzing chemical reactions have long been classified according to the system developed by the Enzyme Commission (EC), no comparable system has been developed or proposed for transport proteins catalyzing transmembrane vectorial reactions. We here propose a comprehensive system, designated the Transport Commission (TC) system, based both on function and phylogeny. The TC system initially categorizes permeases according to mode of transport and energy coupling mechanism, and each category is assigned a one-component TC number (W). The secondary level of classification corresponds to the phylogenetic family (or superfamily) to which a particular permease is assigned, and each family is assigned a two-component TC number (W.X). The third level of classification refers to the phylogenetic cluster within a family (or the family within a superfamily) to which the permease belongs, and each cluster receives a three-component TC number (W.X.Y). Finally, the last level of categorization is based on substrate specificity and polarity of transport, and each entry is assigned a four component TC number (W.X.Y.Z). This system is based on the observation that mode of transport and energy coupling mechanism are fundamental properties of transport systems that very seldom transcend familial lines, but substrate specificity, being readily alterable by point mutations, is a superficial characteristic that often transcends familial lines. The proposed system has the potential to include all known permeases for which sequence data are available and has the flexibility to accommodate the multitude of permeases likely to be revealed by future genome sequencing and biochemical analysis. Major conclusions resulting from our classification efforts are described. The classification system, which will be continuously updated, is available on our World Wide Web site (http:/(/)www-biology.ucsd.edu/ approximately msaier/transport/titlepage.html).