Embryonic pathway signaling leads to induction of epithelial-to-mesenchymal transition. Hedgehog (Hh), Notch, Wnt, and transforming growth factor (TGF)-β signaling can activate epithelial-to-mesenchymal transition (EMT) regulators to induce phenotypic changes through a variety of signaling intermediates. EMT-inducing signals by Snail, Slug, KLF8, Twist, Goosecoid, Foxc1 and -2, or Zeb1 and -2 drive non-mobile epithelial-like cells to acquire more invasive phenotypes. By migrating into the circulatory system, cancer stem cells can translocate to new locations and initiate new metastatic growths. EGF, epidermal growth factor; Fzd, Frizzled; Hh, Hedgehog; HIF, hypoxia-inducible factor; NICD, Notch intracellular domain; Smo, Smoothened; TGF, transforming growth factor.