Invasive cancer cells traffic from the primary tumor ecosystem to distant metastatic sites. Experimental data are reviewed with a focus on cross-signaling between cancer cells and host cells such as myofibroblasts and mesenchymal stem cells. Invasion-associated cellular activities, namely vesicle exocytosis and epithelial to mesenchymal transition, depend on complex networks of signal transduction pathways including activation of tyrosine kinases, the Rab, Rac and Rho family of small GTPases and cadherin signaling. As clinical validation, some cell types or molecules implicated in invasion-associated activities may serve as prognostic/predictive biomarker or as target for patient-tailored therapy.