Cancer malignancy is characterized by cancer cell invasion within local and distant ecosystems. Data from our laboratory are reviewed with a focus on cross-signaling between cancer cells and host cells such as myofibroblasts, mesenchymal stem cells and adipocytes. Invasion-associated cellular activities, namely epithelial to mesenchymal transition, homotypic and heterotypic cell-cell adhesion, cell-matrix adhesion, migration, proteolysis and vesicle exocytosis, depend on branching networks of signal transduction pathways including activation of trimeric G proteins, phosphoinositide 3-kinase, src, signal transducer and activator of transcription and the Rab, Rac and Rho family of small GTPases. The role of proteolysis in invasion is not limited to breakdown of extracellular matrix but also causes cleavage of pro-angiogenic fragments from cell surface glycoproteins. Some cell types or molecules implicated in invasion-associated activities may serve as prognostic biomarker or as target for patient-tailored therapy.