The acquisition of a cell polarity is a crucial requirement for migration, activation, and apoptosis of leukocytes. The polarization of leukocytes involves the formation of two distinct poles: the leading edge--the attachment cell site to the substrate allowing directional movements of the cell--and on the opposite side, the uropod--mostly involved in cell-to-cell interaction and in a variety of leukocyte activities including activation and apoptosis. However, the uropod takes shape in neutrophils, monocytes, and natural killer cells, and the formation of this cell protrusion seems to exert an important role in immune interactions. In fact, the polarization sites of leukocytes are involved in a complex cross-talk between cells and extracellular matrix components, and a number of receptors and counter-receptors crowd in the contact sites to allow efficient cell-to-cell or cell-substrate interaction. The membrane/cytoskeleton interaction plays a crucial role in tuning these activities and in "predisposing" leukocytes to their function through the acquisition of a polarized phenotype. This review is focused on the mechanisms underlying the formation of the leukocyte uropod, the role of cytoskeleton in defining its structure and function, and the involvement of the uropod in the complex interplay between immune cells.