As IAPs are key molecular targets for the development of cancer cell-selective therapeutics, our findings reveal a potential mechanism for a Smac-mimetic IAP-antagonist on TRAIL-mediated signaling, and suggest that modulating IAPs may contribute to enhanced TRAIL efficacy, especially in androgen-independent prostate cancer with high levels of IAPs and constitutively active NF-κB signaling. The gene discussed is NFKB1; the disease is prostate cancer.