Drug resistance in cancer is a complex phenomenon influenced by various mechanisms, including drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, epithelial-mesenchymal transition (EMT), and epigenetic effects. This review outlines the current understanding of these mechanisms and their roles in cancer drug resistance. It discusses how drug resistance develops in cancer cells through processes such as drug inactivation, where cancer cells may not activate drugs properly, leading to resistance. Alterations in drug targets, such as mutations or changes in expression levels, can also lead to resistance. Drug efflux, mediated by ATP-binding cassette (ABC) transporters, is another mechanism by which cancer cells expel drugs. DNA damage repair mechanisms, such as nucleotide excision repair and homologous recombination, can also contribute to resistance. Cell death inhibition, including the inhibition of apoptosis and autophagy, can prevent cancer cell death. EMT is a process that allows cancer cells to become more invasive and resistant to treatment. Epigenetic modifications, such as DNA methylation and histone modification, can also contribute to drug resistance by altering gene expression. Cancer progenitor cells, which are not killed by conventional therapies, may also play a role in drug resistance. The review also discusses the potential of epigenetic therapies in overcoming drug resistance by targeting these mechanisms. Overall, the review highlights the importance of understanding these mechanisms to develop more effective treatments for drug-resistant cancers.Drug resistance in cancer is a complex phenomenon influenced by various mechanisms, including drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, epithelial-mesenchymal transition (EMT), and epigenetic effects. This review outlines the current understanding of these mechanisms and their roles in cancer drug resistance. It discusses how drug resistance develops in cancer cells through processes such as drug inactivation, where cancer cells may not activate drugs properly, leading to resistance. Alterations in drug targets, such as mutations or changes in expression levels, can also lead to resistance. Drug efflux, mediated by ATP-binding cassette (ABC) transporters, is another mechanism by which cancer cells expel drugs. DNA damage repair mechanisms, such as nucleotide excision repair and homologous recombination, can also contribute to resistance. Cell death inhibition, including the inhibition of apoptosis and autophagy, can prevent cancer cell death. EMT is a process that allows cancer cells to become more invasive and resistant to treatment. Epigenetic modifications, such as DNA methylation and histone modification, can also contribute to drug resistance by altering gene expression. Cancer progenitor cells, which are not killed by conventional therapies, may also play a role in drug resistance. The review also discusses the potential of epigenetic therapies in overcoming drug resistance by targeting these mechanisms. Overall, the review highlights the importance of understanding these mechanisms to develop more effective treatments for drug-resistant cancers.