Gadolinium (Gd) and its complexes are utilized widely in industrial and clinical diagnoses. As a rare earth metal ion, free gadolinium (Gd(3+)) in the human body poses neurotoxic risks during its in vivo release and retention. In the central nervous system, astrocytes play a pivotal role in processing toxic metal ions. The present study evaluates the effects of Gd on cellular calcium homeostasis, a common mechanism that causes cell death, and on unfolded protein responses (UPRs), a mechanism for cell survival in response to toxic stimuli in mammalian cells. The experimental results indicate that the influx of extracellular Ca(2+) increases greatly after the exposure of astrocytes to Gd; however, no cell deaths were observed. Further evidence suggests the up-regulated expression of the endoplasmic reticulum (ER)-resident chaperone protein GRP78 by ER stress-mediated signal transductions, specifically the activation of ATF6, eIF2a, and IRE1. These results suggest that Gd promotes Ca(2+) influx, thus triggering UPRs, which can be closely associated to the resistance of astrocytes to Gd-induced cytotoxicity.