TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can induce apoptosis in tumor cells while sparing healthy cells. Over the past three decades, TRAIL has been extensively studied for its potential as an anti-tumor agent, but most attempts have failed. Emerging evidence suggests that TRAIL can also trigger non-canonical signal transduction pathways, which may be detrimental in oncology. Additionally, TRAIL can induce tumor cell motility via Death receptor 5 (DR5), potentially contributing to tumor metastasis. While the pro-apoptotic signaling pathways of TRAIL are well understood, the non-canonical pathway is less explored. This review aims to provide an overview of the current understanding of TRAIL's non-canonical signaling pathways, focusing on the molecular events leading to cell motility and metastasis. TRAIL binding to its agonist receptors, DR4 and DR5, forms multimeric complexes that recruit FADD and caspases, leading to apoptosis. However, TRAIL can also trigger necroptosis through RIPK1-dependent pathways, and induce cell motility and invasion through secondary complexes and nuclear translocation of DR5. TRAIL's non-canonical signaling pathways are regulated by various mechanisms, including receptor dimerization, glycosylation, and post-translational modifications. In physiological contexts, TRAIL plays roles in immune system homeostasis, angiogenesis, and cell differentiation. In diseases, TRAIL is associated with endothelial cell function, lung and heart diseases, and Alzheimer's disease. The molecular mechanisms underlying TRAIL's non-canonical signaling pathways, including cell motility and metastasis, remain largely unknown. This review highlights the complexity of TRAIL's signaling machinery and its implications in both physiological and pathophysiological processes.TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can induce apoptosis in tumor cells while sparing healthy cells. Over the past three decades, TRAIL has been extensively studied for its potential as an anti-tumor agent, but most attempts have failed. Emerging evidence suggests that TRAIL can also trigger non-canonical signal transduction pathways, which may be detrimental in oncology. Additionally, TRAIL can induce tumor cell motility via Death receptor 5 (DR5), potentially contributing to tumor metastasis. While the pro-apoptotic signaling pathways of TRAIL are well understood, the non-canonical pathway is less explored. This review aims to provide an overview of the current understanding of TRAIL's non-canonical signaling pathways, focusing on the molecular events leading to cell motility and metastasis. TRAIL binding to its agonist receptors, DR4 and DR5, forms multimeric complexes that recruit FADD and caspases, leading to apoptosis. However, TRAIL can also trigger necroptosis through RIPK1-dependent pathways, and induce cell motility and invasion through secondary complexes and nuclear translocation of DR5. TRAIL's non-canonical signaling pathways are regulated by various mechanisms, including receptor dimerization, glycosylation, and post-translational modifications. In physiological contexts, TRAIL plays roles in immune system homeostasis, angiogenesis, and cell differentiation. In diseases, TRAIL is associated with endothelial cell function, lung and heart diseases, and Alzheimer's disease. The molecular mechanisms underlying TRAIL's non-canonical signaling pathways, including cell motility and metastasis, remain largely unknown. This review highlights the complexity of TRAIL's signaling machinery and its implications in both physiological and pathophysiological processes.