Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is capable of selectively inducing apoptosis of cancer cells, is a potential targeted drug for cancer therapy. Many clinical trials have verified the safety, tolerability, and therapeutic efficacy of TRAIL or TRAIL agonists in patients. However, the resistance to TRAIL in multiple cancer cells resulted in limited treatment response and poor prognosis. In this review, the molecular mechanisms of TRAIL resistance in cancer cells are summarized. How TRAIL receptors, structure of the cellular membrane, the Protein Kinase B (Akt) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways involve in regulating TRAIL resistance is described. A full understanding of the exact molecular mechanisms of TRAIL resistance in cancer cells could help to design more suitable strategies and new drugs to overcome TRAIL resistance and obtain better therapeutic outcomes.