The Anterior Gradient-2 (AGR2) is an Endoplasmic Reticulum (ER)-resident protein belonging to the Protein Disulfide Isomerase (PDI) family which mediates the formation of disulfide bonds, and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 ' interactome' and discuss the pathological and physiological role of such AGR2 interactions.