Molecular analysis, in vivo and in vitro has identified TRAIL as a central component of anti-cancer networks in the cell. More recently, TRAIL has been shown to be involved in the selective apoptosis of AML cells by histone deacetylase inhibitors (HDACi). Here we summarize findings that the TRAIL pathway is a key factor in the apoptotic action of HDACi, as well as, retinoids and retinoid-combinations.