The principles determining the migration of different cell types may result from their differences in origin, size and shape, function of adhesion receptors, and environmental factors, including the extracellular matrix. Polarized leukocytes (T lymphocytes and dendritic cells) migrating in three-dimensional collagen lattices are small developing a highly dynamic leading edge and a trailing uropod, whereas invasive melanoma cells are larger, highly polarized and less dynamic. In contrast to leukocytes, tumor cells may additionally develop migrating cell clusters maintaining intense cell-cell interaction and cluster polarity. Leukocytes show a speed-oriented, oscillating and directionally unpredictable path profile strongly guided by matrix fibers, while melanoma cells and migrating cell clusters exhibit slow yet highly directional migration. Whereas leukocytes form short-lived interactions with collagen fibers in complete absence of tissue remodeling, melanoma cells and neoplastic cell clusters reorganize the matrix via profound pulling at attachment sites, limited fiber disruption upon detachment, and the shedding of cell surface determinants. Using blocking anti-integrin antibodies, tumor cell migration and migration-associated matrix reorganization were shown to be dependent on β integrin-mediated adhesion, whereas migrating T cells cannot be inhibited by a panel of anti-β1-, β2-, β3-, and α-integrin antibodies, either alone or in combination. Consequently, migrating melanoma cells use focal adhesions of integrins coclustered with cytoskeletal components at contacts with collagen fibers. T cells, however, lack typical focal adhesions, redistribute β1 integrins to the uropod and the focal adhesion kinase to the leading edge. In conclusion, an adhesion-dependent and reorganizing migration type employed by melanoma cells may be distinct from largely integrinindependent and non-reorganizing migration strategies used by leukocytes.