Platinating agents, including cisplatin, carboplatin, and oxaliplatin, have been widely used in cancer treatment for nearly three decades. These agents form cytotoxic lesions on DNA, primarily through the formation of intrastrand and interstrand crosslinks. Resistance to these agents can arise from various cellular adaptations, such as reduced uptake, inactivation by antioxidants like glutathione, and increased DNA repair or tolerance. The review discusses the pathways activated by platinating agents, mechanisms of resistance, and associated clinical toxicities. Cisplatin and carboplatin are extensively used for treating various cancers, but their use is limited by resistance and toxicities. Oxaliplatin, which forms fewer crosslinks, is less toxic but equally potent. The review highlights the involvement of HMG proteins in recognizing and binding to DNA lesions, the role of endoplasmic reticulum stress in apoptosis, and the activation of signaling cascades and transcription factors. Additionally, it covers DNA repair mechanisms, including nucleotide excision repair, mismatch repair, and homologous recombination. The clinical utility of these agents is discussed, along with their toxicities, particularly nephrotoxicity, neurotoxicity, and ototoxicity. The review also explores resistance mechanisms, such as decreased influx or increased efflux of the drugs, and the role of transporters like CTR1, ATP7A, and ATP7B. Finally, it emphasizes the need to overcome resistance and reduce toxicities to improve the effectiveness of platinating agents in cancer treatment.Platinating agents, including cisplatin, carboplatin, and oxaliplatin, have been widely used in cancer treatment for nearly three decades. These agents form cytotoxic lesions on DNA, primarily through the formation of intrastrand and interstrand crosslinks. Resistance to these agents can arise from various cellular adaptations, such as reduced uptake, inactivation by antioxidants like glutathione, and increased DNA repair or tolerance. The review discusses the pathways activated by platinating agents, mechanisms of resistance, and associated clinical toxicities. Cisplatin and carboplatin are extensively used for treating various cancers, but their use is limited by resistance and toxicities. Oxaliplatin, which forms fewer crosslinks, is less toxic but equally potent. The review highlights the involvement of HMG proteins in recognizing and binding to DNA lesions, the role of endoplasmic reticulum stress in apoptosis, and the activation of signaling cascades and transcription factors. Additionally, it covers DNA repair mechanisms, including nucleotide excision repair, mismatch repair, and homologous recombination. The clinical utility of these agents is discussed, along with their toxicities, particularly nephrotoxicity, neurotoxicity, and ototoxicity. The review also explores resistance mechanisms, such as decreased influx or increased efflux of the drugs, and the role of transporters like CTR1, ATP7A, and ATP7B. Finally, it emphasizes the need to overcome resistance and reduce toxicities to improve the effectiveness of platinating agents in cancer treatment.