It is generally accepted that electrochemical gradients of monovalent ions across the plasma membrane, created by the coupled function of pumps, carriers and channels, are involved in the maintenance of resting and action membrane potential, cell volume adjustment, intracellular Ca(2+ )handling and accumulation of glucose, amino acids, nucleotides and other precursors of macromolecular synthesis. In the present review, we summarize data showing that side-by-side with these classic functions, modulation of the intracellular concentration of monovalent ions in a physiologically reasonable range is sufficient to trigger numerous cellular responses, including changes in enzyme activity, gene expression, protein synthesis, cell proliferation and death. Importantly, the engagement of monovalent ions in regulation of the above-listed cellular responses occurs at steps upstream of Ca(2+) (i) and other key intermediates of intracellular signaling, which allows them to be considered as second messengers. With the exception of HCO (3) (-) -sensitive soluble adenylyl cyclase, the molecular origin of sensors involved in the function of monovalent ions as second messengers remains unknown.