Cell motility is important for tissue homeostasis and plays a central role in various pathologies, notably inflammation and cancer. Research into the critical processes involved in cell migration has so far mostly focused on cell adhesion and proteolytic degradation of the extracellular matrix. However, pharmacological interference with these processes only partially blocks cell motility in vivo. In this review we summarize the arising evidence that the mechanical properties of the cell body have a major role to play in cell motility--especially in a low-adhesion, amoeboid-like migration mode in three-dimensional tissue structures. We summarize the processes determining cell mechanics and discuss relevant measurement technologies including their applications in medical cell biology.