Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been extensively studied for its preferential ability to induce apoptosis of cancer cells. Beyond the cytotoxic capacity of TRAIL, new physiological and pathological roles for TRAIL have been identified, and there is now growing evidence supporting its involvement in the development of obesity and diabetes. This review summarizes the most recent findings associating TRAIL with obesity and diabetes in both humans and experimental settings. We also present and discuss some of the reported controversies behind TRAIL signaling and function. Understanding TRAIL mechanism(s) in vivo and its involvement in disease may lead to novel strategies to combat the growing pandemic of obesity and diabetes worldwide.