Dendritic cells (DCs) are critical regulators of immune responses and central to antigen presentation. DC maturation and migration are governed by alterations of cytosolic Ca²⁺. Moreover, DC functions are under powerful regulation of the phosphatidylinositol-3-kinase (PI3K) pathway, which suppresses proinflammatory cytokine production. PI3K downstream targets include Akt kinases. The present study explored whether Akt2 influences Ca²⁺-signaling and Ca²⁺-dependent functions in DCs. Experiments were performed in DCs isolated from bone marrow of wild-type (akt2^+/+) and knockout (akt2^-/-) mice. Akt2-deficient DCs demonstrated normal differentiation and lipopolysaccharide (LPS, 1 mg/ml)-induced maturation, according to the CD86 and MHCII expression on CD11c positive cells, analyzed by FACS, as well as normal production of IL-12 and IL-6, measured by ELISA. However, in transwell chamber transmigration assays, we observed impaired migration of LPS-matured akt2^-/-DCs in response to the chemokine CCL21 (25 ng/ml). CCL21 (75 ng/ml)-induced increase in cytosolic Ca²⁺ [Ca²⁺]_i in LPS-matured DCs, measured by Fura-2 fluorescence, was also significantly decreased in akt2^-/- DCs. Since chemokine-induced Ca²⁺ increase is known to be mediated through store-operated Ca²⁺ (SOC) channels, SOC entry was analyzed in akt2^+/+ and akt2^-/- DCs upon store depletion by inhibition of the Ca²⁺ -ATPase SERCA with thapsigargin (1 mM). As a result both SOC entry and release of Ca²⁺ from intracellular stores were impaired in akt2^-/- DCs. In conclusion, Akt2 positively regulates DC migration, presumably through upregulation of Ca²⁺ release and Ca²⁺ entry through SOC channels.