The ubiquitous second messenger calcium (Ca2+) interacts with numerous cellular proteins to regulate physiological processes. Ca2+ also participates in a variety of diseases, including hepatitis B virus (HBV) infection. HBV infection is a major cause of fibrosis, cirrhosis, and hepatocellular carcinoma. Recent studies have demonstrated that HBV infection elevates levels of intracellular Ca2+ and this elevation is primarily dependent on the HBV protein HBX. The activation of Ca2+ signaling contributes to viral replication in HBV-infected cells. The importance of Ca2+ signaling in HBV infection makes controlling intracellular Ca2+ a promising therapeutic target. Early studies have suggested that binding cytosolic Ca2+ or inhibiting Ca2+ channels reduces viral replication, but current research is largely derived from in vitro cellular models and needs to be confirmed in animal models and human patients. The influence Ca2+ signaling has on the subsequent development of HBV-associated diseases, like hepatitis, is also largely unexplored.