Dendritic cells (DC) are the sentinels of the immune system, linking innate with adaptive responses. The functional responses of DC are subject to complex regulation and serve as targets for pathogens. Ca2+-mediated signal transduction pathways serve a central regulatory role in DC responses to diverse antigens, including TLR ligands, intact bacteria, and microbial toxins. This review summarizes the major mechanisms of Ca2+-signaling that DC utilize to regulate maturation and antigen presentation, including a Ca2+-calmodulin (CaM)-CaM kinase II pathway that is localized to phagosomes and is targeted by the human intracellular pathogen, Mycobacterium tuberculosis. Restoration of functional Ca2+ signaling in DC may provide a novel mechanism to enhance therapy and promote vaccine efficacy to infectious diseases, including tuberculosis.