Since calcium-signaling regulates specific and fundamental cellular processes, it represents the ideal target of viral proteins, in order for the virus to control cellular functions and favour its persistence, multiplication and spread. A detailed analysis of reports focused on the impact of viral proteins on calcium-signaling has shown that virus-related elevations of cytosolic calcium levels allow increased viral protein expression (HIV-1, HSV-1/2), viral replication (HBx, enterovirus 2B, HTLV-1 p12(I), HHV-8, EBV), viral maturation (rotavirus), viral release (enterovirus 2B) and cell immortalization (EBV). Interestingly, virus-induced decreased cytosolic calcium levels have been found to be associated with inhibition of immune cells functions (HIV-1 Tat, HHV-8 K15, EBV LMP2A). Finally, several viral proteins are able to modulate intracellular calcium-signaling to control cell viability (HIV-1 Tat, HTLV-1 p13(II), HCV core, HBx, enterovirus 2B, HHV-8 K7). These data point out calcium-signaling as a key cellular target for viral infection and should stimulate further studies exploring new calcium-related therapeutic strategies.