The decrease in postural muscle fiber size, diminishing of their contractile properties, slow-to-fast shift in myosin heavy chain expression pattern are known to be the main consequences of gravitational unloading. The Ca2+ role in these processes has been studied for about 20 years. Ingalls et al. [J Appl Physiol 87(1):382–390, 1999] found the resting Ca2+ level increase in soleus fibers of hindlimb unloaded mice. Results obtained in our laboratory showed that systemic or local application of nifedipine (L-type Ca2+ channels' blocker) prevents Ca2+ accumulation in fibers. Thus, activation of dihydropyridine calcium channels can be supposed to promote resting Ca2+ loading under disuse. So, calcium-dependent signaling pathways may play an important role in the development of some key events observed under unloading. Since 90th the increased activities of Ca2+-dependent proteases (calpains) were considered as the crucial effect of hypogravity-induced muscle atrophy, which was proved later. We observed maintenance of titin and nebulin relative content in soleus muscle under unloading combined with Ca2+ chelators administration. Nifedipine administration was shown to considerably restrict the slow-to-fast transition of myosin heavy chains (MHC) under unloading (at the RNA level and at the protein level as well). To clarify the role of calcineurin/NFAT signaling system in MHC pattern transition under unloading, we blocked this pathway by cyclosporine A application. Hereby, we demonstrated that calcineurin/NFAT pathway possesses a stabilizing function counteracting the myosin phenotype transformation under gravitational unloading.