Urothelial carcinoma of the bladder (UCB) shows different biological outcomes, diverse biological propensities for invading the muscularis as well as epithelial-to-mesenchymal transition (EMT), a dynamic key event during developmental processes, wound healing, and tissue repair. The EMT core molecules include EMT-activating transcription factors (EMT-ATFs), and a host of downstream effectors and target genes including extracellular inducers and growth factors. Here, we describe molecular regulatory determinants of mesenchymal-to-epithelial transition (MET) and more specifically EMT that allows a subset of urothelial cancer cells to gain mesenchymal traits with self-renewal potential. EMT accelerates tumor progression and poses a clinical challenge to anticancer therapies. Targeting the populations of tumor-initiating cells and those with a metastable phenotype provide the basis for the development of more reliable risk assessment of tumor progression and risk, and better treatment strategies of UCB.