The recently increasing number of atomic structures for active transporters has not only revealed strong conservation in the architecture of sequence-unrelated transporter families, but also identified a unifying element called the 'inverted repeat topology,' which is found in nearly all transporter folds to date. Indeed, most membrane transporters consist of two or more domains with similar structure, so-called repeats. It is tempting to speculate that transporters have evolved by duplication of one repeat followed by gene fusion and modification events. An intriguing question is, whether recent genes encoding such a 'half-transporter' still exist as independent folding units. Although it seems likely that the evolution of membrane transport proteins, which harbor internal repeats, is linked to these minimal structural building blocks, their identification in the absence of structural data represents a major challenge, as sequence homology is not an issue. In this review we discuss two protein families, the DedA family and the SWEET family, being potential half-transporters and putative ancestors for two of the most abundant secondary transporter families, the MFS family and the LeuT-fold family.