Survival of human and animal cells requires avoidance of excessive alterations of cell volume. The osmolarity amassed by cellular accumulation of organic substances must be compensated by lowering cytosolic ion concentrations. The Na+/K+ ATPase extrudes Na+ in exchange for K+, which can permeate the cell membrane through K+ channels. K+ exit generates a cell-negative potential difference across the cell membrane, driving the exit of anions such as Cl-. The low cytosolic Cl- concentrations counterbalance the excess cellular osmolarity by organic substances. Cell volume regulation following cell swelling involves releasing ions through activation of K+ channels and/or anion channels, KCl-cotransport, or parallel activation of K+/H+ exchange and Cl-/HCO3- exchange. Cell volume regulation following cell shrinkage involves accumulation of ions through activation of Na+,K+,2Cl- cotransport, Na+/H+ exchange in parallel to Cl-/HCO3- exchange, or Na+ channels. The Na+ taken up is extruded by the Na+/K+ ATPase in exchange for K+. Shrunken cells further accumulate organic osmolytes such as sorbitol and glycerophosphorylcholine, and monomeric amino acids by altered metabolism and myoinositol (inositol), betaine, taurine, and amino acids by Na+ coupled transport. They release osmolytes during cell swelling. Challenges of cell volume homeostasis include transport, hormones, transmitters, and drugs. Moreover, alterations of cell volume participate in the machinery regulating cell proliferation and apoptotic cell death. Deranged cell volume regulation significantly contributes to the pathophysiology of several disorders such as liver insufficiency, diabetic ketoacidosis, hypercatabolism, fibrosing disease, sickle cell anemia, and infection.