Targeting cancer cells is one of the challenges of current treatment strategies. TRAIL represents a promising therapeutic approach and over the past decades there was an increased interest in targeting TRAIL signaling to treat cancer. Indeed, TRAIL can specifically target cancer cells and exhibits very low cytotoxicity towards normal cells. However, rapidly accumulating experimental evidence has started to shed light on multiple factors which induce resistance against TRAIL in cancer cells. This resistance consists of various mechanisms including downregulation of death receptors and caspase-8 and overexpression of decoy receptors as well as antiapoptotic factors such as members of Bcl-2 family. Even if several studies focused on elucidating those resistance mechanisms, there still remain gray areas that need to be fully elucidated. Thus, therapeutic approaches could consist of targeting both resistance signaling pathways and TRAIL signaling to enhance TRAIL therapy efficiency.