Upregulated polyamine biosynthesis and high polyamine transport activity are hallmarks of aggressive cancers. Efforts to inhibit polyamine biosynthesis via inhibition of the proto-oncogene ornithine decarboxylase (ODC) have been disappointing in the clinic (e.g., difluoromethylornithine, DFMO) due to unforeseen compensatory mechanisms involving polyamine import. In short, DFMO-treated cells were able to meet their polyamine requirements via import of polyamines from extracellular sources. Polyamine transport inhibitors (PTIs) have been developed to work synergistically with DFMO to induce sustained polyamine depletion. The goal of this review is to summarize the efforts to develop effective PTI agents. A new terminology is introduced to better describe molecules which enter cells via a transport system (i.e., transporton) versus molecules which interact with the transport system but show no net entry into the cell (i.e., anti-transporton). Both transportons and anti-transportons will inhibit the uptake of native polyamines, and a clear distinction was necessary to properly describe this class of compounds. Molecular designs involving polycations with discrete spacing and number of charges were shown to be very effective PTI agents. Arylpolyamines, lipopolyamines, antibodies specific for heparan sulfate proteoglycans and cationic proteins have all shown activity as PTIs. Future PTI design will be shaped by the extensive structure–activity relationships developed to date.