PTR2/POT/NPF are a family of primarily proton coupled transporters that belong to the major facilitator super family and are found across most kingdoms of life. They are involved in uptake of nutrients, hormones, ions and several orally administered drug molecules. A wealth of structural and functional data is available for this family; the similarity between the protein structural features have been discussed and investigated in detail on several occasions, however there are no reports on the unification of substrate information. In order to fill this gap, we have collected information about substrates across the entire PTR2/POT/NPF family in order to provide key insights into what makes a molecule a substrate and whether there are common features among confirmed substrates. This review will be of particular interest for researchers in the field trying to probe the mechanisms responsible for the different selectivity of these transporters at a molecular resolution, and to design novel substrates.