Our results revealed that the treatment of melanoma cells with imiquimod evokes a rapid increase in intracellular Ca2+ release and the activation of PERK and IER1α as well as the degradation of calpain, and anticipates a central role for ER stress‐associated pathways in the modulation of imiquimod‐induced apoptosis of melanoma cells. The gene discussed is EIF2AK3; the disease is melanoma.