The continuing efforts to exploit the death receptor agonists, such as the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), for cancer therapy, have largely been impaired by the anti-apoptotic and pro-survival signalling pathways leading to drug resistance. Cell migration, invasion, differentiation, immune evasion and anoikis resistance are plastic processes sharing features of the epithelial-to-mesenchymal transition (EMT) that have been shown to give cancer cells the ability to escape cell death upon cytotoxic treatments. EMT has recently been suggested to drive a heterogeneous cellular environment that appears favourable for tumour progression. Recent studies have highlighted a link between EMT and cell sensitivity to TRAIL, whereas others have highlighted their effects on the induction of EMT. This review aims to explore the molecular mechanisms by which death signals can elicit an increase in response heterogeneity in the metastasis context, and to evaluate the impact of these processes on cell responses to cancer therapeutics.