Tirapazamine is the second clinical anticancer drug (after porfiromycin) that functions primarily as a hypoxia-selective cytotoxin. Hypoxic cells in tumours are relatively resistant to radiotherapy and to some forms of chemotherapy and are also biologically aggressive, thus representing an important target population in oncology. Tirapazamine undergoes metabolism by reductases to form a transient oxidising radical that can be efficiently scavenged by molecular oxygen in normal tissues to re-form the parent compound. In the absence of oxygen, the oxidising radical abstracts a proton from DNA to form DNA radicals, largely at C4' on the ribose ring. Tirapazamine can also oxidise such DNA radicals to cytotoxic DNA strand breaks. It therefore shows substantial selective cytotoxicity for anoxic cells in culture (typically approximately 100-fold more potent than under oxic conditions) and for the hypoxic subfraction of cells in tumours. Preclinical studies showed enhanced activity of combinations of tirapazamine with radiation (to kill oxygenated cells) and with conventional cytotoxics, especially cisplatin (probably through inhibition of repair of cisplatin DNA cross-links in hypoxic cells). Phase II and III clinical studies of tirapazamine and cisplatin in malignant melanoma and non-small cell lung cancer suggest that the combination is more active than cisplatin alone and preliminary results with advanced squamous cell carcinomas of the head and neck indicate that tirapazamine may enhance the activity of cisplatin with fractionated radiotherapy.