Multicellular organisms require apoptosis whereby the human body eliminates unnecessary and/or damaged cells. Apoptosis, or programmed cell death, can indeed be considered as a constitutive anti-cancer mechanism that seems to be defective in more than 50% of cancers. Molecular insights on the biology of the apoptotic process have led to the development of new anti-cancer strategies aiming at recovering and stimulating this process. Preclinical and clinical studies of our and other groups have demonstrated that targeting the extrinsic apoptotic pathway by various death receptors agonists is a safe and effective anti-cancer strategy, which thus may become a new cornerstone of cancer therapy. Here, we review the most recent acquisitions and patents on TRAIL or TRAIL mimetics, as well as the combination therapies that could be used with them.