The matrix metalloproteinases(MMP)-2 and -9, also known as the gelatinases have been long recognized as major contributors to the proteolytic degradation of extracellular matrix during tumor invasion. In the recent years, a plethora of non-matrix proteins have also been identified as gelatinase substrates thus significantly broadening our understanding of these enzymes as proteolytic executors and regulators in various physiological and pathological states including embryonic growth and development, angiogenesis and tumor progression, inflammation, infective diseases, degenerative diseases of the brain and vascular diseases. Although the effect of broad-spectrum inhibitors of MMPs in the treatment of cancer has been disappointing in clinical trials, novel mechanisms of gelatinase inhibition have been now identified. Inhibition of the association of the gelatinases with cell-surface integrins appears to offer highly specific means to target these enzymes without inhibiting their catalytic activity in multiple cell types including endothelial cells, tumor cells and leukocytes. Here, we review the multiple functions of the gelatinases in cancer, and especially their role in the tumor cell migration and invasion.