Pemetrexed and related 5-substituted pyrrolo[2,3-d]pyrimidine antifolates are substrates for the ubiquitouslyexpressedreduced folate carrier (RFC), and the proton-coupled folate transporter(PCFT) and folate receptors (FRs) which are more tumor-selective.A long-standing goal has been to discover tumor-targeted therapeuticsthat draw from one-carbon metabolic vulnerabilities of cancer cellsand are selective for transport by FRs and PCFT over RFC. This evidence concerns the gene SLC46A1 and cancer.