Epithelial-mesenchymal transition (EMT) is a major process controlling multiple developmental events. The mesenchyme appeared as a transient state in diploblasts more than 800 million years ago. EMT has been conserved through evolution to control morphogenetic events, such as the formation of the three primary germ layers during gastrulation. Interestingly, related signal transduction pathways are remarkably conserved in many species. In the animal kingdom, EMT controls the intercellular adhesion machinery and its associated cytoskeleton. EMT pathways are also intimately involved in determination and differentiation programs, and are reactivated in adult tissues following injury or exposure to toxic agents. EMT is likely to play a role in early steps of carcinoma invasion, enabling blood or lymph vessel intravasation. Mesenchymal-like carcinoma cells undergo a mesenchymal to epithelial transition at distant sites from the primary tumor, and eventually form macrometastases. The mesenchymal-like state of cancer cells confers stemness, protection from cell death, immune escape and, most importantly, resistance to conventional and targeted therapies. Current strategies based on the EMT concept are aimed at designing new therapeutic approaches that interfere with the plasticity of carcinoma cells.