Adiponectin, which exists in serum in three major complexes including trimer, hexamer, and the high molecular weight (HMW) form, has strong insulin sensitizing, anti-inflammatory and anti-diabetic functions. Different adiponectin complexes exert tissue-specific biological functions and activate distinct signaling pathways. In this review, we summarize our current understanding on the mechanisms regulating adiponectin multimerization. We also describe the major target tissues in which distinct adiponectin multimers exert their functional roles. Finally, we discuss the potential involvement of endoplasmic reticulum stress and mitochondrial stress in diet-induced adiponectin downregulation and highlight the roles of Disulfide bond A oxidoreductase-like protein (DsbA-L) in the prevention of endoplasmic reticulum stress and promotion of adiponectin multimerization, stability, and function.