Over the past decade, the reactivation of TWIST embryonic transcription factors has been described as a frequent event and a marker of poor prognosis in an impressive array of human cancers. Growing evidence now supports the premise that these cancers hijack TWIST's embryonic functions, granting oncogenic and metastatic properties. In this review, we report on the history and recent breakthroughs in understanding TWIST protein functions and the emerging role of the associated epithelial-mesenchymal transition (EMT) in tumorigenesis. We then broaden the discussion to address the general contribution of reactivating embryonic programs in cancerogenesis.