The occurrence of metastases is the hallmark of cancer. Development of metastasis severely affects prognosis and survival. It limits or discourages therapeutic interventions since no therapies are available to block or prevent cancer invasion. In order to invade, epithelial cancer cells need to penetrate through the basement membrane (BM) and remove extra-cellular matrix (ECM) tissue boundaries. In this context, proteases play a key role since they can either degrade or process the ECM components and thereby support cancer cell invasion. Laminin-5 (Ln-5) is an ECM protein, expressed predominantly in the BM structure, that promotes static adhesion and hemidesmosome formation. However, it also stimulates cell migration and/or invasion after having been cleaved by matrix metalloproteinases (MMPs) such as MMP-2 and MT1-MMP. Based on its dual functions, it would be intriguing to elucidate the role that Ln-5 plays in cancer cell motility and metastasis. One possibility is that MMPs, secreted by cancer cells or by neighbouring stromal cells, can cleave the gamma2 chain of Ln-5 deposited along the advancing edge of tumors. Ln-5, and in particular its gamma2 chain, has been found to be preferentially expressed in the cytoplasm of epithelial human cancer cells located at the advancing edge of the tumor. Such a distribution, which is restricted only to malignancies, suggests that the gamma2 chain may be implicated in epithelial cancer growth and invasion. Although the clinical significance of this finding is not yet clear, it seems often to be associated with a more aggressive and invasive cancer phenotype. This article will review the current body of evidence implicating the Ln-5 molecule, and in particular its gamma2 chain, as an important player in the tumor cascade and progression to metastatic disease. This will then be followed by a discussion of the presented data and its limitations. Finally, suggestions will be provided to improve the current state of knowledge in the field and future implications will be briefly discussed.