Chemotherapy resistance in cancer remains a major challenge due to cancer heterogeneity, genetic factors, and complex cellular biology. This review explores the molecular mechanisms underlying resistance to three chemotherapeutic agents—docetaxel, carboplatin, and doxorubicin—in various cancer models. These drugs induce epigenetic, transcriptional, post-transcriptional, and metabolic changes that contribute to drug resistance. Understanding these mechanisms is crucial for developing more effective cancer therapies. Docetaxel inhibits microtubule depolymerization, leading to cell cycle arrest and apoptosis. Resistance to docetaxel is associated with altered transcriptional regulation, increased expression of survival pathways like mTOR, and changes in redox systems. Proteomic changes, including upregulation of ABCB1 and downregulation of p27, contribute to resistance. Metabolic alterations, such as changes in glycolysis and sphingolipid metabolism, also play a role in resistance. Carboplatin induces DNA damage and cell cycle arrest, but resistance is linked to altered transcriptional regulation, including changes in CREB and FOXM1 expression. Proteomic changes, such as overexpression of MDR1 and PIM1, contribute to resistance. Metabolic alterations, including changes in choline and ceramide metabolism, are also involved in resistance. Doxorubicin induces DNA damage and apoptosis, but resistance is associated with altered transcriptional regulation, including changes in BAX/BCL2 ratio and miRNA expression. Proteomic changes, such as upregulation of ABC transporters and SUMOylation, contribute to resistance. Metabolic alterations, including changes in glycolysis and sphingolipid metabolism, also play a role in resistance. The review highlights the importance of understanding these molecular mechanisms to develop strategies for overcoming chemotherapy resistance. Targeting epigenetic, transcriptional, and metabolic pathways offers potential for improving chemotherapy efficacy. Future research should focus on combination therapies, precision medicine, and novel drug delivery systems to enhance treatment outcomes.Chemotherapy resistance in cancer remains a major challenge due to cancer heterogeneity, genetic factors, and complex cellular biology. This review explores the molecular mechanisms underlying resistance to three chemotherapeutic agents—docetaxel, carboplatin, and doxorubicin—in various cancer models. These drugs induce epigenetic, transcriptional, post-transcriptional, and metabolic changes that contribute to drug resistance. Understanding these mechanisms is crucial for developing more effective cancer therapies. Docetaxel inhibits microtubule depolymerization, leading to cell cycle arrest and apoptosis. Resistance to docetaxel is associated with altered transcriptional regulation, increased expression of survival pathways like mTOR, and changes in redox systems. Proteomic changes, including upregulation of ABCB1 and downregulation of p27, contribute to resistance. Metabolic alterations, such as changes in glycolysis and sphingolipid metabolism, also play a role in resistance. Carboplatin induces DNA damage and cell cycle arrest, but resistance is linked to altered transcriptional regulation, including changes in CREB and FOXM1 expression. Proteomic changes, such as overexpression of MDR1 and PIM1, contribute to resistance. Metabolic alterations, including changes in choline and ceramide metabolism, are also involved in resistance. Doxorubicin induces DNA damage and apoptosis, but resistance is associated with altered transcriptional regulation, including changes in BAX/BCL2 ratio and miRNA expression. Proteomic changes, such as upregulation of ABC transporters and SUMOylation, contribute to resistance. Metabolic alterations, including changes in glycolysis and sphingolipid metabolism, also play a role in resistance. The review highlights the importance of understanding these molecular mechanisms to develop strategies for overcoming chemotherapy resistance. Targeting epigenetic, transcriptional, and metabolic pathways offers potential for improving chemotherapy efficacy. Future research should focus on combination therapies, precision medicine, and novel drug delivery systems to enhance treatment outcomes.