Epithelial-to-mesenchymal transition (EMT) is a fundamental cellular phenomenon that plays an intrinsic role in development, tissue repair, and cancer progression. EMT is tightly regulated by transcription factors that alter gene expression to promote epithelial to mesenchymal phenotype. EMT is also regulated by a diverse array of cytokines and growth factors whose activities are deregulated during malignancy. EMT enables tumor cells to exist in various intermediate states along the epithelial-mesenchymal phenotypic axis that transit from cancer stem cells (CSCs) to circulating tumor cells (CTCs). Recent studies have revealed the importance of CSCs in tumor promotion, invasion and metastasis. The relapsed tumors encompass CSCs which are resistant to radiotherapy and chemotherapy. In this review, we have summarized our current understanding of the molecular mechanisms that regulate EMT induced CSC phenotype. We have highlighted studies implicating the function of TGF-β, Wnt, and Notch regulated non-coding RNAs in driving EMT promoting CSC self-renewal. Finally, we discuss how the EMT and CSCs cause drug resistance with the hope to overcome such resistance as a possible approach for cancer treatment.