Congenital Disorders of Glycosylation (CDG) are rare inherited diseases causing glycosylation defects responsible for severe growth and psychomotor retardations in patients. Whereas most genetic defects affect enzymes directly involved in the glycosylation process, like glycosyltransferases or sugar transporters, recent findings revealed the impact of gene mutations on proteins implicated in both Golgi vesicular trafficking and ion homeostasis. TMEM165 is one of these deficient Golgi proteins found in CDG patients whose function in the secretory pathway has been deduced from several recent studies using TMEM165 deficient mammalian cells or yeast cells deficient in Gtd1p, the yeast TMEM165 ortholog. These studies actually confirm previous observations based on both sequence and predicted topology of this transmembrane protein and the phenotypes of human and yeast cells, namely that TMEM165 is very probably a transporter involved in ion homeostasis. Whereas the exact function of TMEM165 remains to be fully characterized, several studies hypothesize that TMEM165 could be a Golgi localized Ca/H antiporter. However, recent data also support the role of TMEM165 in Golgi Mn homeostasis then arguing for a putative role of Mn transporter for TMEM165 essential to achieve the correct N-glycosylation process of proteins in the secretory pathway. This manuscript is a review of the current state of knowledge on TMEM165 deficiencies in Congenital Disorders of Glycosylation as well as new data on function of TMEM165 and some speculative models on TMEM165/Golgi functions are discussed.