Calcium (Ca2+) homeostasis is essential for cellular signaling and protein trafficking. Viruses are comparatively simple organisms that leverage the availability of host cellular mechanisms for viral replication, including the manipulation of cellular Ca2+ dynamics-related processes. We review the dependence of HIV on cellular Ca2+ to promote viral replication, including stabilization of viral protein complexes in clinically latent HIV infected cells. We also discuss some of the general reliance of cellular Ca2+ homeostasis on viral propagation across several viruses. We discuss viral manipulations of cellular Ca2+ regulation for viral replication, specifically for viral assembly, complex stability, and disassembly. We close with an exploration of therapeutic opportunities via Ca2+ homeostasis disruption to mediate dysregulation of viral complex formation for viral peptide antigen presentation. Thereby, we aim to unlock a novel strategy to achieve an antiviral effect by modulating host-cell regulatory processes.