Both stromal and epithelial cells in tumors exhibit marked heterogeneity that can affect communication within and between tissue layers resulting in alterations in cell proliferation, survival and death. Many of these interactions are cooperative rather than competitive. The various signaling axes represent a complex network of altered ligand/receptor availability that can be modified to alter growth and progression. A more complete understanding of cellular complexity in both stromal and epithelial tissues should allow us to model these intercellular communications with a view to identifying key nodes that can be coordinately modulated to restrict tumor growth.