Signaling via TNF-R1 mediates pleiotropic biological outcomes ranging from inflammation and proliferation to cell death. Previous reports demonstrated that pro-survival signaling emanates from membrane resident TNF-R1 complexes (complex I) while only internalized TNF-R1 complexes are capable for DISC formation (complex II) and thus, apoptosis induction. Internalized TNF-R1 containing endosomes undergo intracellular maturation towards lysosomes, resulting in activation and release of Cathepsin D (CtsD) into the cytoplasm. We recently revealed HSP90 as target for proteolytic cleavage by CtsD, resulting in cell death amplification. In this study, we show that extrinsic cell death activation via TNF or TRAIL results in HSP90 beta degradation. Co-incubation of cells with either TNF or TRAIL in combination with the HSP90 beta inhibitor KUNB105 but not HSP90 alpha selective inhibition promotes apoptosis induction. In an attempt to reveal further downstream targets of combined TNF-R1 or TRAIL-R1/-R2 activation with HSP90 beta inhibition, we identify HIF1 alpha and validate its ligand: inhibitor triggered degradation. Together, these findings suggest that selective inhibition of HSP90 isoforms together with death ligand stimulation may provide novel strategies for therapy of inflammatory diseases or cancer, in future.