High rates of metastasis correlate with a poor prognosis of cancer. Cell migration and invasion are two major steps in the metastatic cascade. Both of them depend on the extracellular matrix composition. The present study compares migratory and invasive activity of a mouse melanoma (B16) and a human breast cancer cell line (MDA-MB-231) on a basal membrane-like matrix composed of collagen IV (92.1%), laminin (0.7%) and fibronectin (7.2%) and a dermis-like matrix composed of collagen I (96.1%), collagen IV (3.2%) and laminin (0.7%). Cell migration was monitored employing time lapse video microscopy, and invasion was tested by determining the number of cells crossing matrix-coated filter-membranes. Both the mouse melanoma and the human breast cancer cells migrated vividly on a basal lamina-like matrix (B16: 0.40.03 mm min^-1; MDA-MB: 0.710.07 mm min^-1) which they did not invade. By contrast, they slowed down drastically (B16: 0.250.03 mm min^-1; MDA-MB: 0.420.07 mm min^-1) and became invasive on a dermis-like matrix. Interestingly, the cells were clearly more adhesive on the basal lamina-like matrix. Inhibition of the Na⁺/H⁺ exchanger (NHE1) by cariporide (HOE642) slowed migration down by up to 40%, stopped invasion nearly completely and reduced adhesion by up to 50% regardless of the matrix composition used. In order to quantify matrix digestion in close proximity to the cell surface, in situ zymography assays taking advantage of the proteolytically activated fluorescent dyes BSA-Bodipy and BSA-FITC were performed. The activation of the fluorescent dyes that were incorporated in the matrix revealed that, in both cell lines, total matrix digestion in close proximity to the cell surface more than doubled when seeded on the dermis-like matrix. On both matrices NHE1 inhibition reduced digestive activity by about 30%. The present observations demonstrate that adhesion, migration, invasion, and extracellular matrix digestion require NHE1 activity. They also indicate that it is the extracellular matrix itself that determines (i) whether cells migrate on or invade a matrix and (ii) to what extent the extracellular matrix is digested. The collagen I / laminin composition and/or a higher matrix density/rigidity stimulate the cells to choose a proteolytic/invasive program over a motile program. By facilitating cell adhesion NHE1 activity enables the cells to detect different components of the extracellular matrix via recognition by adhesion receptors. Outside-in signaling by these receptors could then modulate processes that affect migration and/or invasion.