Emerging evidence points towards a key role of the extracellular matrix (ECM) during tumor progression and therapy resistance. Paradoxically, in today's routine of cancer management the ECM is not taken into account. It is the aim of the present review to broaden our understanding of the mechanisms of therapy resistance, taking the ECM as a presumptive central regulator. The stromal ecosystem drives the accumulation of ECM at the invasion front. Therefore, we address the question whether the detection of ECM signatures in histopathology and biofluids may help predicting therapy resistance and determining the prognosis of cancer. Since the ECM is an attractive target for tumor therapy, current therapeutic strategies in preclinical or clinical development will be discussed.