Tenascin-C is an adhesion modulatory extracellular matrix molecule that is highly expressed in the microenvironment of most solid tumors. High tenascin-C expression reduces the prognosis of disease-free survival in patients with some cancers. The possible role of tenascin-C in tumor initiation and progression is addressed with emphasis on underlying signaling mechanisms. How tenascin-C affects malignant transformation, uncontrolled proliferation, angiogenesis, metastasis and escape from tumor immunosurveillance is summarized. Finally, we discuss how the phenotypes of tenascin-C knock-out mice may help define the roles of tenascin-C in tumorigenesis and how this knowledge could be applied to cancer therapy.