The CaBP family of EF-hand containing small Ca(2+)-binding proteins have recently emerged as important regulators of multiple targets essential to normal neuronal function in the mammalian central nervous system. Of particular interest are CaBP7 and CaBP8, abundantly expressed brain proteins that exhibit the greatest sequence divergence from other family members. In this study, we have analysed their sub-cellular localisations in a model neuronal (Neuro2A) cell line and show that both proteins exhibit a membrane distribution distinct from the other CaBPs and consistent with localisation to the trans-Golgi network (TGN). Furthermore, we show that their localisation to the TGN critically depends upon an unusual predicted C-terminal transmembrane domain that if deleted or disrupted has dramatic consequences for protein targeting. CaBP7 and 8, therefore, possess a targeting mechanism that is unique amongst the CaBPs that may contribute to differential functional Ca(2+)-sensing by these family members.