Since the serendipitous discovery of the biological action of platinum coordination complexes in 1965 (Rosenberg et al., 1965), cis-diamminedichloroplatinum (cis-DDP) has developed from an agent that caused filamentous growth of bacteria to the largest-selling cancer chemotherapeutic drug. Today, cis-DDP is firmly established as a drug of high potency in the treatment of testicular, ovarian, bladder and head and neck carcinoma and is gaining popularity in the treatment of a variety of other tumors as a result of the development of new therapeutic regimes. cis-DDP is a neutral square-planar coordination compound (Fig. 1). The two chloride ligands are stable at the chloride concentration of the extracellular matrix but after diffusion into a cell, the lower chloride concentration permits loss of chloride from the drug. The drug becomes an aquated, charged electrophile which reacts with nucleophilic sites on cellular macromolecules. Extensive evidence has implicated DNA as the critical target (Roberts and Thomson, 1979). Lesions in DNA include interstrand cross-links, intrastrand cross-links and DNA-protein crosslinks. These bifunctional reactions are critical to the toxic action of the drug because monofunctional analogues show no therapeutic activity. In addition, the trans isomer (trans-DDP) which also reacts bifunctionally with DNA, is therapeutically inactive, trans-DDP produces both DNA-interstrand cross-links and DNA-protein cross-links but is sterically restricted in the type of intrastrand cross-links it could feasibly produce. This has implicated intrastrand cross-links as important to the activity of cis-DDP. In early studies, cis-DDP-induced DNA interstrand cross-links and DNA-protein cross-links were extensively studied, not because they represented the major lesions in DNA but rather that techniques were available for their measurement. Accordingly, in many experiments, the production of DNA-interstrand cross-links was correlated with cell toxicity (Zwelling et al., 1979; Erickson et al., 1981) even though other experiments suggested that more significant lesions existed (Filipski et al., 1980; Strandberg et al., 1982). Analysis of the relative frequency of interstrand cross-links led to the conclusion that they represented less than 1% of the platination of DNA (Roberts and Friedlos, 1981; Pera et al., 1981; Eastman, 1982a). This, therefore, set the stage for a complete characterization of all the lesions in DNA induced by cis-DDP. This has now been accomplished. This paper will describe how this was achieved and what conclusions have resulted. However, it still remains to determine the relative significance of each lesion to the therapeutic activity of the drug.