The endoplasmic reticulum (ER), one of the organelles of eukaryotic cells, is not only important for the translation and folding of proteins using a sophisticated quality control system that only allows native proteins to exit the ER, but also mediates targeting of proteins to the plasma membrane and the secretion of proteins. Moreover, as the major calcium store of a eukaryotic cell, the ER plays an important role in intracellular calcium signaling. Protein disulfide isomerase (PDI) and the ER oxidoreductin 1 (Ero1) are major players in disulfide bond formation and reshuffling. TMX4, one of the thioredoxin-related transmembrane proteins which are members of the PDI family that otherwise consists only of soluble proteins, is upregulated in cell lines derived from cancerous skin. Thus, the aims of this thesis were to investigate whether (i) protein levels of TMX and TMX4 are also aberrant in cancerous skin (melanoma), (ii) elevated levels of TMX or TMX4 have any effect on Ero1, and (iii) the secretion of vascular endothelial growth factor (VEGF), a major angiogenic factor, is enhanced, thereby ensuring tumor growth. Moreover, the sub-organellar localization of the two ER-resident proteins, TMX and TMX4, was examined in order to elucidate their biological roles. To this end, TMX and TMX4 levels in melanoma samples were compared with those in healthy skin, the oxidation state of Ero1 in TMX- and TMX4-transfected HEK293 cells was investigated, the VEGF secretion patterns by TMX- and TMX4-transfected HeLa cells were examined, and finally, subcellular localization of TMX and TMX4 in a human melanoma cell line was studied by immunofluorescence. The results revealed that TMX4, but not TMX, tended to be upregulated in melanoma, and may change the oxidation state of Ero1. However, overexpression of either TMX or TMX4 altered the secretion of VEGF. Additionally, TMX and TMX4 are localized in distinct domains of the ER.