During epithelial-mesenchymal transition (EMT)--a morphogenetic program involved in several steps of embryogenesis--epithelial cells lose many of their epithelial characteristics and acquire properties typical of mesenchymal cells. The mechanisms underlying this transition are frequently reactivated during tumor progression, generating cells with enhanced motility and invasiveness. Several in vitro and in vivo studies point to a role of EMT in metastatic dissemination of epithelial tumors. In addition, recent data show that EMT-inducing transcription factors, such as the Twist proteins, can inhibit crucial oncosuppressive responses that normally counteract the emergence of a cell population with aberrant mitogenic activity, by triggering either apoptosis or premature senescence. Abrogation of these failsafe cellular mechanisms is a prerequisite for malignant progression. Together, these observations suggest that EMT could play a major pathological role by favoring both tumor development and metastatic dissemination. We examine the main data supporting this hypothesis and discuss its potential clinical implications.