Cisplatin and carboplatin are among the most active and widely used cytotoxic anticancer drugs. However, the acquisition or presence of resistance significantly undermines the curative potential of these drugs against many malignancies. Multiple potential mechanisms of resistance have been identified at the cellular and molecular levels. Alterations in cellular pharmacology, including decreased drug accumulation, increased cellular thiol levels and increased repair of platinum–DNA damage, have been observed in numerous model systems. More recently, it has become apparent that an enhanced capacity to tolerate cisplatin-induced damage may also contribute to resistance. Alterations in proteins that recognise cisplatin–DNA damage (mismatch repair and high-mobility group (HMG) family proteins) and in pathways that determine sensitivity to apoptosis may contribute to damage tolerance. It remains to be determined whether any of these mechanisms contribute significantly to resistance in the clinical setting. Ongoing biochemical modulation and translational correlative trials should clarify which specific mechanisms are most relevant to clinical cisplatin resistance. Such investigations have the potential to improve the ability to predict likelihood of response and should identify potential targets for pharmacological or molecular intervention.