Representative important factors and concepts implicated in drug resistance and relapses. Various intracellular factors can account for impaired OCC cell response to chemotherapy drugs, including changes in the bioavailability of a drug or its active metabolites at the target site (decreased uptake or increased efflux), inability of cells to repair DNA damage which can lead to increase tolerance, and defects in cell ability to signal DNA damage response to downstream effectors targets to trigger cell death. Altered drug pharmacodistribution and pharmacodynamics in the host also impact on drug response. The selective pressure exerted by drugs combined with tumor cell heterogeneity (often a result of tumor genomic instability) is also a driving force for drug resistance. Tumors can develop resistance via regulation of their microenvironment, e.g., by remodeling the extracellular matrix, deregulating cancer cell-endothelial cell/immune infiltrating cell interactions, leading to enhanced angiogenesis, hypoxia, and resistance to cell death. In this context, epithelial-mesenchymal transition (EMT) and the reverse process mesenchymal-epithelial transition (MET), both are critical process for cancer progression to metastasis and homing in distant site contribute to drug resistance via various mechanisms, including induction of cell heterogeneity and selection of rare cancer stem cell (CSC) variants with intrinsic resistance to chemotherapy.