The environment within which cancer cells exist is a key determinant of tumor survival and growth. The extracellular matrix that comprises the tumor stroma provides vital cues that control cell phenotype and enable the tumor to thrive. Moreover, emerging evidence reveals the importance of the extracellular matrix in permitting colonization of secondary tumor sites by creating a specific environmental niche tailored to enhance metastatic cell survival. Tenascin-C is an extracellular matrix glycoprotein whose expression is specifically induced in many different types of cancer and where it drives processes such as tumor cell growth, angiogenesis, immune modulation and metastatic fitness. Here, we review the molecular mechanisms underlying the pleiotrophic role of tenascin-C in disease pathology and highlight the impact of these data on the development of new strategies to diagnose and treat cancer.