Platinating agents, including cisplatin, carboplatin, and oxaliplatin, are widely used in cancer treatment. These agents form platinum-DNA crosslinks, which are thought to be their primary cytotoxic mechanism. However, resistance to these agents is common, with mechanisms including reduced drug uptake, increased DNA repair, and detoxification by antioxidants like glutathione. Resistance can also arise from cellular adaptations such as increased DNA repair or tolerance. The mechanisms of resistance involve various pathways, including the nucleotide excision repair (NER), mismatch repair (MMR), and homologous recombination (HR). Additionally, transporters like CTR1, ATP7A, and ATP7B play a role in cisplatin resistance by affecting drug uptake and efflux. Toxicities associated with platinating agents include nephrotoxicity, neurotoxicity, and ototoxicity. These side effects can be dose-limiting, particularly in pediatric patients. Oxaliplatin is associated with more severe neurotoxicity than cisplatin or carboplatin. Anti-oxidants and other strategies are being explored to mitigate these toxicities. Carboplatin and oxaliplatin have fewer side effects than cisplatin, with myelosuppression and neurotoxicity being the main dose-limiting factors, respectively. Resistance to platinating agents is multifactorial, involving both genetic and environmental factors. The role of transporters, DNA repair mechanisms, and antioxidant systems in resistance is increasingly recognized. Understanding these mechanisms is crucial for developing strategies to overcome resistance and reduce toxicity in cancer patients. Despite their importance, platinating agents face challenges in achieving their full therapeutic potential due to resistance and toxicity. Ongoing research aims to improve the efficacy and safety of these agents through targeted therapies and better patient selection.Platinating agents, including cisplatin, carboplatin, and oxaliplatin, are widely used in cancer treatment. These agents form platinum-DNA crosslinks, which are thought to be their primary cytotoxic mechanism. However, resistance to these agents is common, with mechanisms including reduced drug uptake, increased DNA repair, and detoxification by antioxidants like glutathione. Resistance can also arise from cellular adaptations such as increased DNA repair or tolerance. The mechanisms of resistance involve various pathways, including the nucleotide excision repair (NER), mismatch repair (MMR), and homologous recombination (HR). Additionally, transporters like CTR1, ATP7A, and ATP7B play a role in cisplatin resistance by affecting drug uptake and efflux. Toxicities associated with platinating agents include nephrotoxicity, neurotoxicity, and ototoxicity. These side effects can be dose-limiting, particularly in pediatric patients. Oxaliplatin is associated with more severe neurotoxicity than cisplatin or carboplatin. Anti-oxidants and other strategies are being explored to mitigate these toxicities. Carboplatin and oxaliplatin have fewer side effects than cisplatin, with myelosuppression and neurotoxicity being the main dose-limiting factors, respectively. Resistance to platinating agents is multifactorial, involving both genetic and environmental factors. The role of transporters, DNA repair mechanisms, and antioxidant systems in resistance is increasingly recognized. Understanding these mechanisms is crucial for developing strategies to overcome resistance and reduce toxicity in cancer patients. Despite their importance, platinating agents face challenges in achieving their full therapeutic potential due to resistance and toxicity. Ongoing research aims to improve the efficacy and safety of these agents through targeted therapies and better patient selection.