Abstract Hyperosmotic stress initiates a variety of compensatory and adaptive responses, which either serve to restore near-normal volume or remodel and reinforce the cell structure to withstand the physical challenge. The latter response is brought about by the reorganization of the cytoskeleton; however, the underlying mechanisms are not well understood. Recent research has provided major breakthroughs in our knowledge about the link between message and structure, i.e. between signalling and cytoskeletal remodelling, predominantly in the context of cell migration. The major components of this progress are the in-depth characterization of Rho family small GTPases, master regulators of the cytoskeleton, and the discovery of the actin-related protein 2/3 complex, a signalling-sensitive structural element of the actin polymerization machinery. The primary aim of this review is to find the place of these novel and crucial players in osmotically induced (volume-dependent) remodelling of the cytoskeleton. We aim to address three questions: (1) What are the major structural changes in the cytoskeleton under hyperosmotic conditions? (2) Are the Rho family small GTPases (Rho, Rac and Cdc42) regulated by osmotic stress, and if so, by what mechanisms? (3) Are Rho GTPases involved, as mediators, in major adaptive responses, including cytoskeleton rearrangement, changes in ion transport and genetic reprogramming? Our answers will show how fragmentary our current knowledge is in these areas. Therefore, this overview has been written with the hardly disguised intention that it might foster further research in this field by highlighting some intriguing questions.