The hypoxic cells common in solid tumors (because of their inefficient blood supply) limit the effectiveness of radiotherapy and many cytotoxic drugs. Nontoxic prodrugs that generate active species in hypoxic tissue by selective bioreduction have long been explored, and the first examples, representing a variety of different chemistries, have now reached advanced clinical trials. In the process, a great deal has been learnt about the properties that such drugs require to be successful, notably, efficient extravascular diffusion, appropriate reduction chemistry and kinetics, and an effective biological profile of the activated species, including a good bystander effect. The critical importance of prodrug diffusion and techniques to quantify this have assisted the development of models to predict the killing of tumor cells, which promises to help accelerate new drug evaluation. A cell cycle-independent mechanism of killing by the released cytotoxin is also a potential advantage, although it is likely that much of the killing will be when out-of-cycle hypoxic cells reoxygenate and resume division.