TRAIL, a member of the TNF superfamily, is known for inducing apoptosis in tumor cells while sparing healthy cells. However, emerging evidence suggests that TRAIL can also trigger non-canonical signaling pathways that may be detrimental for its use in oncology. These pathways can lead to tumor cell motility and metastasis, particularly through DR5. While the pro-apoptotic signaling of TRAIL is well understood, the non-canonical pathways remain less explored. TRAIL can activate NF-κB, leading to increased tumor growth and inflammation. TRAIL also induces cell migration and metastasis via DR5, contributing to tumor progression. TRAIL's signaling involves complex interactions with receptors, leading to the formation of DISC and secondary complexes like the FADDosome or MISC. These complexes can activate NF-κB, promoting survival and pro-tumoral effects. TRAIL can also induce necroptosis in certain conditions, involving RIPK1 and MLKL. Additionally, TRAIL can influence cell fate decisions through stochastic events and receptor distribution. TRAIL's role in the immune system includes maintaining lymphocyte homeostasis and regulating inflammation. It plays a crucial role in viral clearance and tumor immune surveillance. TRAIL's non-apoptotic functions may also contribute to immune responses against pathogens or cancer. TRAIL is involved in various diseases, including autoimmune disorders, and may have therapeutic potential in autoimmune therapy. However, TRAIL's pro-tumoral properties, such as promoting cell migration and metastasis, pose challenges for its use in oncology. TRAIL's signaling pathways are complex, involving multiple receptors and signaling molecules, and understanding these pathways is essential for developing effective therapies.TRAIL, a member of the TNF superfamily, is known for inducing apoptosis in tumor cells while sparing healthy cells. However, emerging evidence suggests that TRAIL can also trigger non-canonical signaling pathways that may be detrimental for its use in oncology. These pathways can lead to tumor cell motility and metastasis, particularly through DR5. While the pro-apoptotic signaling of TRAIL is well understood, the non-canonical pathways remain less explored. TRAIL can activate NF-κB, leading to increased tumor growth and inflammation. TRAIL also induces cell migration and metastasis via DR5, contributing to tumor progression. TRAIL's signaling involves complex interactions with receptors, leading to the formation of DISC and secondary complexes like the FADDosome or MISC. These complexes can activate NF-κB, promoting survival and pro-tumoral effects. TRAIL can also induce necroptosis in certain conditions, involving RIPK1 and MLKL. Additionally, TRAIL can influence cell fate decisions through stochastic events and receptor distribution. TRAIL's role in the immune system includes maintaining lymphocyte homeostasis and regulating inflammation. It plays a crucial role in viral clearance and tumor immune surveillance. TRAIL's non-apoptotic functions may also contribute to immune responses against pathogens or cancer. TRAIL is involved in various diseases, including autoimmune disorders, and may have therapeutic potential in autoimmune therapy. However, TRAIL's pro-tumoral properties, such as promoting cell migration and metastasis, pose challenges for its use in oncology. TRAIL's signaling pathways are complex, involving multiple receptors and signaling molecules, and understanding these pathways is essential for developing effective therapies.