Unraveling the genetic programs that drive -metastasis may offer insights into how to limit or prevent this deadly aspect of cancer progression. Our recent studies indicate that tumor cell metastasis involves the activity of the transcription factor, Twist, which regulates epithelial-mesenchymal transition and early embryonic morphogenesis. Here, we review the Twist signaling pathway during normal development and discuss how the transcription factor Twist and the epithelial-mesenchymal transition program impinge their biological functions during tumor metastasis.