Cell movement within three-dimensional tissues is a cycling multistep process that requires the integration of complex biochemical and biophysical cell functions. Different cells solve this challenge differently, which leads to differences in migration strategies. Migration principles established for leukocytes share many characteristics with those described for ameba of the lower eukaryote Dictyostelium discoideum. The hallmarks of amoeboid movement include a simple polarized shape, dynamic pseudopod protrusion and retraction, flexible oscillatory shape changes, and rapid low-affinity crawling. Amoeboid crawling includes haptokinetic adhesion-dependent as well as biophysical migration mechanisms on or within many structurally and functionally different substrates. We describe central aspects of amoeboid movement in leukocytes and the implications for leukocyte crawling and positioning strategies within interstitial tissues.