At the August meeting of the American Chemical Society in Washington, DC, Zhaochun Ma and John-Stephen Taylor of Washington University (St. Louis, MO) reported a strategy that uses disease-specific gene sequences to activate cytotoxic drugs. Their system employs two oligonucleotides, one that binds to a disease-specific trigger sequence and is coupled to an inactive prodrug, and the other that binds to an adjacent sequence and is coupled to a pro-drug activator. They used imidazole to release the cytotoxic drug p-nitrophenyl from its ester, a reaction that is a key step in activation of a recently reported class of daunorubicin pro-drugs. The presence of all three components triggered formation of a complex that brought the prodrug in contact with the catalytic activator. The prodrug was then activated enzymatically and in multiple cycles, but in the presence of a single base pair mismatch, drug release was 7.5-fold less efficient. Taylor cautions that “We have yet to determine whether the prodrug releasing system is stable in plasma and inside cells and efficient enough.…This might be the most challenging part of the work.”