Metastatic relapse is responsible for 90% of cancer-related deaths. The process of distant spreading is a cascade of events that is regulated in a highly complex manner; one cellular phenomenon underlying all the events is cytoskeletal reorganisation. Despite the fact that the ability to leave the primary site and establish a viable mass in a distant site is a hallmark of cancer, targeting cytoskeletal reorganisation is an emerging field. In this review we describe the key signalling pathways controlling cytoskeletal reorganisation and the current targeted therapies against the "druggable" nodes. Finally, we discuss potential implications of trial design that can play a role in detecting the specific activity of this drug class.