The epithelial to mesenchymal transition (EMT) converts epithelial cells into migratory and invasive cells and is a fundamental event in morphogenesis. Although its relevance in the progression of cancer and organ fibrosis had been debated until recently, the EMT is now established as an important step in the metastatic cascade of epithelial tumors. The similarities between pathological and developmental EMTs validate the embryo as the best model to understand the molecular and cellular mechanisms involved in this process, identifying those that are hijacked during the progression of cancer and organ degeneration. Our ever-increasing understanding of how transcription factors regulate the EMT has revealed complex regulatory loops coupled to posttranscriptional and epigenetic regulatory programs. The EMT is now integrated into the systemic activities of whole organisms, establishing links with cell survival, stemness, inflammation, and immunity. In addition, the EMT now constitutes a promising target for the treatment of cancer and organ-degenerative diseases.