Osmotic perturbations, occurring frequently under physiological and pathological conditions, alter cell size/volume and function. To protect cellular homeostasis, cell osmo- and volume-sensing mechanisms activate volume compensatory processes. The plasma membrane plays a prominent role in cell volume regulation by mediating the selective transport of extra- and intracellular osmolytes. The function of the membrane-enclosed cytoplasm in osmosensing and cell volume homeostasis is much less appreciated. We present current concepts and discuss evidence of cell volume sensors with emphasis on the hydrogel nature of the mammalian cytoplasm and its intrinsic osmosensitivity.