Since its initial identification, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to be capable of selectively inducing apoptosis in cancer cells. However, translation of the encouraging preclinical studies of this cytokine into the clinic has been restricted by its extremely short half-life, the presence of resistant cancer cell populations, and its inefficient in vivo delivery. Recently, there has been exceptional progress in developing novel formulations to increase the circulatory half-life of TRAIL and new combinations to treat cancers that are resistant to TRAIL. In particular, TRAIL-based nanotherapies offer the potential to improve the stability of TRAIL and prolong its half-life in plasma, to specifically deliver TRAIL to a particular target site, and to overcome resistance to TRAIL. The aim of this review is to provide an overview of the state-of-the art drug delivery systems that are currently being tested or developed to improve the biological attributes of TRAIL-based therapies.