This review traces the development of a series of potent and selective antitumour benzothiazoles from the discovery of the initial lead compound, 2-(4-amino-3-methylphenyl)benzothiazole (DF 203) in 1995 to the identification of a clinical candidate, Phortress, scheduled to enter Phase 1 trials in Q1 2004 under the auspices of Cancer Research U.K. Advances in our understanding of the mechanism of action of this unique series of agents are described and can be summarised as follows: selective uptake into sensitive cells followed by Arylhydrocarbon Receptor (AhR) binding and translocation into the nucleus, induction of the cytochrome P450 isoform (CYP) 1A1, conversion of the drug into an electrophilic reactive intermediate and formation of extensive DNA adducts resulting in cell death. Our understanding of this mechanistic scenario has played a crucial role in the drug development process, most notably in the synthesis of fluorinated DF 203 analogues to thwart deactivating oxidative metabolism (5F 203) and water-soluble prodrug design for parenteral administration. Aspects of mechanism of action studies, in vitro and in vivo screening, synthetic chemistry and pharmacokinetics are reviewed here.