The rTS gene was discovered because it codes for a complementary (antisense) RNA to the messenger RNA for thymidylate synthase (TS). It was later shown that rTS also encodes 2 proteins, rTSa and rTSb. Recently, it has become apparent that rTSb overexpression can cause the downregulation of TS protein in a colon cancer cell line through the production of > or = 1 previously unknown signaling molecules. This observation signified the presence of a previously unidentified signaling pathway. The existence of a signaling pathway that can regulate TS protein levels and the widespread expression of the rTSb protein suggests that a new target for drug development may be on the horizon. This review describes the relationship between the rTS and TS genes and the known and potential effects of rTS RNAs and rTS proteins. We also present the structure of an identified TS downregulatory compound that may serve as a lead compound for development.