Leukocyte migration is crucial during the development of the immune system and in the responses to infection, inflammation, and tumor rejection. The migratory behavior of leukocytes under physiological and pathological conditions as well as the extracellular cues and intracellular machinery that control and guide migration have been studied thoroughly. The cytoskeleton of leukocytes is extremely versatile, bearing characteristic features that enable these cells to migrate under conditions of flow through narrow spaces and onto target tissues. What makes the cytoskeleton machinery so extraordinary is not so much its molecular composition, but its flexibility which allows it to display a unique combination of responses to the extracellular medium and a rapid regulation of the architecture of its components. This review focuses on the cytoskeleton of the leukocyte. Its molecular components and the regulation of their assembly and organization are discussed. Furthermore, it highlights aspects of the regulation of the leukocyte cytoskeleton that confer flexibility to these cells in order to perform their specific tasks. Finally, different subcellular structures such as the immunological synapse, the uropod of migrating leukocytes, and the phagosome displayed by phagocytic cells are discussed in detail. The relationship of the leukocyte with its environment occurs through different kinds of receptors that interact with ligands that are soluble, fixed on the membrane of other cells, or immobilized on the extracellular matrix. The impact of receptor-ligand binding on the functional responses and the rearrangement of the cytoskeleton is also examined.