In any organism, very precisely adjusted interaction and exchange of information between cellsis continuously required. These cooperative interactions involve numerous cytokines, acting throughcorresponding sets of cell-surface receptors. The transforming growth factor β (TGF-β)superfamily includes a variety of structurally related multifunctional cytokines that play criticalroles in maintaining cellular homeostasis and controlling cell fate. Response of a cell to a specificsignal it receives should depend upon the current state of the environment, including concentrationsof biologically relevant ions. One of the most biologically active ions, calcium, acts upon a specificcalcium signaling system that operates over a wide temporal range and regulates many cellularprocesses in continuous "cross-talk" with the TGF-β signaling system. In additionto that, the structural and dynamical properties of TGF-β molecules, along with detected directinteraction of them with the biologically relevant cations suggest another level of fine regulationof TGF-β activity. The fact that both mono- and divalent cations bind in the same low-affinitysites implies that some competition of cations for interaction with TGF-β can also occur in vivo,contributing to the diversity of TGF-β biological functions.