The mammalian peptide transporter, PepT1, is a member of the Proton-coupled Oligopeptide Transporter (POT) superfamily of integral membrane proteins. The POT family function by coupling the bulk uptake of short chain peptides to the inwardly directed proton motive force present across the plasma membrane in eukaryotes and inner membrane of prokaryotes. POT family of transporters range in size from ~45 – 75 kDa and contain either 12 or 14 transmembrane helices. The smaller members of the family, which are mostly found in prokaryotes, consist almost entirely as a hydrophobic bundle of helices that reside within the membrane. The larger members of the family are mammalian in origin and whilst still maintaining the same conserved transmembrane core of 12 helices, have an additional polar domain that sits on the outside of the membrane. Substantial progress has recently been made in determining the crystal structures of the bacterial members of the POT family, in particular understanding how they bind and transport peptides across the membrane. However, the role of the extra cellular domain, found only in PepT1 and PepT2, still remains unresolved. We have recently determined the crystal structure for this domain from PepT1 at 2.2 Å enabling the construction of a hybrid model of the mammalian PepT1 transporter. Combined with in vivo functional data, a role for this domain in transport is proposed, revealing intriguing mechanistic insights into the difference between the bacterial and mammalian POT family transporters with important implications for understanding peptide transport in mammalian cells.