Cancer cell plasticity is a phenomenon that allows cancer cells to change their phenotype in response to alterations in their microenvironment. This flexibility promotes tumor progression and facilitates the emergence of therapy-resistant cells. Plasticity of cancer stem cells is critical for their ability to help tumors overcome sensitivity to therapies and metastasize. Epigenetic modifications like DNA methylation, histone modifications, and acetylation lead to epithelial-mesenchymal transition (EMT) or dedifferentiation and contribute to tumor invasion and drug resistance. EMT is associated with the acquisition of more motile mesenchymal traits while dedifferentiation allows cells to switch to a less differentiated state, leading to the loss of original cell gene expression and phenotype, and the acquisition of a new phenotype, all in an attempt to favorably adapt to changing microenvironments, particularly when exposed to therapeutic agents. Therapeutic resistance can be overcome by targeting these pathways, and more precisely by countering the associated plasticity. This will require targeting not just the players: genes and other molecular markers/factors, but also the underlying epigenetic events. Transdifferentiation is yet another phenomenon that can potentially be exploited to overcome resistance by transforming tumor cells into a non-drug-resistant state. Understanding these mechanisms, particularly the complexity of interactions and epigenetic regulation, will hold the key to better cancer treatment and patient outcomes.