In-depth analysis of how TRAIL signals through death receptors to induce apoptosis in cancer cells usinghigh throughput technologies has added new layers of knowledge. However, the wealth of information has alsohighlighted the fact that TRAIL induced apoptosis may be impaired as evidenced by experimental findingsobtained from TRAIL resistant cancer cell lines. Overwhelmingly, increasing understanding of TRAIL mediatedapoptosis has helped in identifying synthetic and natural compounds which can restore TRAIL induced apoptosisvia functionalization of either extrinsic or intrinsic pathways. Increasingly it is being realized that biologicallyactive phytochemicals modulate TRAIL induced apoptosis, as evidenced by cell-based studies. In this review wehave attempted to provide an overview of how different phytonutrients have shown efficacy in restoring apoptosisin TRAIL resistant cancer cells. We partition this review into how the TRAIL mediated signaling landscapehas broadened over the years and how TRAIL induced signaling machinery crosstalks with autophagic proteinnetworks. Subsequently, we provide a generalized view of considerable biological activity of coumarins against awide range of cancer cell lines and how coumarins (psoralidin and esculetin) isolated from natural sources haveimproved TRAIL induced apoptosis in resistant cancer cells. We summarize recent updates on piperlongumine,phenethyl isothiocyanate and luteolin induced activation of TRAIL mediated apoptosis. The data obtained frompre-clinical studies will be helpful in translation of information from benchtop to the bedside.