The processes of physiologic and malignant invasion use the same cellular pathways, albeit under differential regulation. Critical signaling messages can be initiated through cell-cell and cell-substratum contact, as well as using autocrine and paracrine activation. Cancer cells are known for their flexibility and autocrine functions, however, they still rely on a battery of important signaling events. The interaction between the tumor cell and the stroma provides an important signaling milieu and target zone for molecular therapeutic intervention. It is now recognized that malignant invasion requires that interaction for optimal signaling and function. New technologies are now available to allow more rapid dissection of these pathways and characterization of unique regulatory sites for therapeutic gain.