<jats:p>The specific transporters involved in maintenance of blood pH homeostasis in cephalopod molluscs have not been identified to date. Using in situ hybridization and immunohistochemical methods, we demonstrate that Na<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup>-ATPase ( soNKA), a V-type H<jats:sup>+</jats:sup>-ATPase ( soV-HA), and Na<jats:sup>+</jats:sup>/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>cotransporter ( soNBC) are colocalized in NKA-rich cells in the gills of Sepia officinalis. mRNA expression patterns of these transporters and selected metabolic genes were examined in response to moderately elevated seawater Pco<jats:sub>2</jats:sub>(0.16 and 0.35 kPa) over a time course of 6 wk in different ontogenetic stages. The applied CO<jats:sub>2</jats:sub>concentrations are relevant for ocean acidification scenarios projected for the coming decades. We determined strong expression changes in late-stage embryos and hatchlings, with one to three log2-fold reductions in soNKA, soNBCe, socCAII, and COX. In contrast, no hypercapnia-induced changes in mRNA expression were observed in juveniles during both short- and long-term exposure. However, a transiently increased ion regulatory demand was evident during the initial acclimation reaction to elevated seawater Pco<jats:sub>2</jats:sub>. Gill Na<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup>-ATPase activity and protein concentration were increased by ∼15% during short (2–11 days) but not long-term (42-days) exposure. Our findings support the hypothesis that the energy budget of adult cephalopods is not significantly compromised during long-term exposure to moderate environmental hypercapnia. However, the downregulation of ion regulatory and metabolic genes in late-stage embryos, taken together with a significant reduction in somatic growth, indicates that cephalopod early life stages are challenged by elevated seawater Pco<jats:sub>2</jats:sub>.</jats:p>