2 Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF 3 superfamily that can lead to the induction of apoptosis in tumor or infected cells. However, activation 4 of TRAIL signaling may also trigger non-apoptotic pathways in cancer and in non-transformed cells, 5 i.e. immune cells. Here, we review the current knowledge on non-canonical TRAIL signaling. The 6 biological outcomes of TRAIL signaling in immune and malignant cells is presented and explained, 7 with a focus on the role of TRAIL for natural killer (NK) cell function. Furthermore, we highlight the 8 technical difficulties in dissecting the precise molecular mechanisms involved in the switch between 9 apoptotic and non-apoptotic TRAIL signaling. Finally, we discuss the consequences thereof for a 10 therapeutic manipulation of TRAIL in cancer and possible approaches to bypass these difficulties.