Adiponectin circulates in blood in multiple isoforms. High molecular weight (HMW) adiponectin is thought to be most biologically active and promotes glucose uptake, insulin sensitivity, and fatty acid oxidation. In obesity, adiponectin isoform formation is disrupted, leading to an inverse association between metabolic disease and HMW and total adiponectin. Adiponectin isoforms also function as acute-phase reactants influencing inflammation in acute and chronic disease. Interestingly, adiponectin and mortality have a U-shaped association. Unfortunately, data concerning adiponectin and its pathophysiologic function conflict. This is predominantly due to difficulties in adequate measurement of adiponectin isoforms and lack of a gold standard. In this review we provide a general overview of the formation and function of adiponectin and its isoforms under physiologic conditions. We highlight the ways adiponectin isoform formation is disrupted in obesity and its ensuing pathologic conditions. Furthermore, we will elaborate on the role of adiponectin isoforms as inflammatory proteins with respect to cardiac and kidney disease and discuss the association of adiponectin with mortality. Finally, we will provide a historical perspective on the measurement of adiponectin isoforms, current limitations, and future challenges.