In embryonic development and throughout life, there are some cells can exhibit phenotypic plasticity. Phenotypic plasticity is the ability of cells to differentiate into multiple lineages. In normal development, plasticity is highly regulated whereas cancer cells re-activate this dynamic ability for their own progression. The re-activation of these mechanisms enables cancer cells to acquire a cancer stem cell (CSC) phenotype- a subpopulation of cells with increased ability to survive in a hostile environment and resist therapeutic insults. There are several contributors fuel CSC plasticity in different stages of disease progression such as a complex network of tumour stroma, epidermal microenvironment and different sub-compartments within tumour. These factors play a key role in the transformation of tumour cells from a stable condition to a progressive state. In addition, flexibility in the metabolic state of CSCs helps in disease progression. Moreover, epigenetic changes such as chromatin, DNA methylation could stimulate the phenotypic change of CSCs. Development of resistance to therapy due to highly plastic behaviour of CSCs is a major cause of treatment failure in cancers. However, recent studies explored that plasticity can also expose the weaknesses in CSCs, thereby could be utilized for future therapeutic development. Therefore, in this review, we discuss how cancer cells acquire the plasticity, especially the role of the normal developmental process, tumour microenvironment, and epigenetic changes in the development of plasticity. We further highlight the therapeutic resistance property of CSCs attributed by plasticity. Also, outline some potential therapeutic options against plasticity of CSCs. Graphical Abstract .