An elevated expression of matrix metalloproteinases (MMPs) has been correlated with the growth and metastasis of preexisting tumors. The latest data, however, suggest that MMPs, by promoting genomic instability, are directly involved in the early stages of cell transformation from normalcy to malignancy and in incipient cancer. Here, we discuss these novel findings and present a novel concept of a proteolysis-driven oncogenesis. We have placed the emphasis of our review on the membrane type-1 matrix metalloproteinase (MT1-MMP)-induced chromosome instability which leads to the transition from normalcy to malignancy.