Invasion, the hallmark of malignancy, consists in the translocation of tumour cells from the initial neoplastic focus into neighbouring host tissues, and also allows tumour cells to penetrate vessel endothelium and enter the circulation to form distant metastasis. A histological pattern found at the periphery of carcinomas is the presence of individual malignant cells detached from the tumour mass and staying independently within the interstitial matrix of the stroma. While they are readily identified by the pathologist as invading malignant cells, their relationship with the compact-appearing portions of the tumour as well as the mechanism underlying the development of this pattern are not immediately evident at histological level. There is growing evidence suggesting that this change in tumour tissue architecture takes place through a peculiar phenotype modulation known as epithelial-mesenchymal transition (EMT). The essential features of EMT are the disruption of intercellular contacts and the enhancement of cell motility, thereby leading to the release of cells from the parent epithelial tissue. The resulting mesenchymal-like phenotype is suitable for migration and, thus, for tumour invasion and dissemination, allowing metastatic progression to proceed. Although the molecular bases of EMT have not been completely elucidated, several interconnected transduction pathways and a number of signalling molecules potentially involved have been identified. These include growth factors, receptor tyrosine kinases, Ras and other small GTPases, Src, beta-catenin and integrins. Most of these pathways converge on the down-regulation of the epithelial molecule E-cadherin, an event critical in tumour invasion and a 'master' programmer of EMT. E-cadherin gene is somatically inactivated in many diffuse-type cancers such as lobular carcinoma of the breast and diffuse gastric carcinoma, in which neoplastic cells through the entire tumour mass have lost many of their epithelial characteristics and exhibit a highly invasive, EMT-derived histological pattern. E-cadherin down-modulation is also seen in solid, non-diffuse-type cancers at the tumour-stroma boundary where singly invading, EMT-derived tumour cells are seen in histological sections. In this latter scenario, E-cadherin loss and EMT could be transient, reversible processes possibly regulated by the tumour microenvironment and, as a matter of fact, neoplastic cells that have undergone EMT during invasion seem to regain E-cadherin expression and their epithelial, cohesive characteristics at the secondary foci. Since the molecules involved in EMT represent potential targets for pharmacological agents, these findings open new avenues for the control of metastatic spread in the treatment of malignancies.