Metastatic spread and acquired or intrinsic resistance to existing therapies form the two major obstacles in cancer treatment. Accumulating evidence indicates that cancer growth, metastasis, and the response to therapy are strongly affected by integrin-mediated interactions with the extracellular matrix (ECM) in the tumor microenvironment. Indeed, altered expression levels of various integrins has been associated with poor differentiation, increased metastasis, and decreased overall and recurrence-free survival after radio- or chemotherapy in different types of cancer. Recent evidence indicates that the role of specific integrins in cancer progression and treatment response depends on the spectrum of oncogenic mutations present in cancer cells. In this PharmSight, we discuss several examples of such cross talk between integrins and oncogenes that may point to new avenues for cancer therapy.