Adiponectin is a protein hormone mainly secreted by adipose tissue that regulates energy homeostasis and glucose and lipid metabolism. Compared with other adipose‐derived hormones, adiponectin is very abundant in plasma and is proposed to be a convenient biomarker for many diseases. A large number of in vitro and in vivo studies support the beneficial effects of adiponectin on metabolic syndrome, diabetes, and atherosclerosis. However, the protective actions were challenged occasionally by the controversies in its role in inflammation and in the specific functions of its different conformations. Recently, quite a few reports suggested that the antiapoptotic activity of adiponectin might contribute to its therapeutic potential during ischemia/reperfusion injury in vivo, whereas some studies demonstrated that adiponectin induced apoptosis both in vitro and in vivo. Herein, this review attempts to summarize the present consensus and divergence and to provide possible alternative and/or complementary explanations for this apparent paradox.