Tumor necrosis factor-alpha (TNFα) is an inflammatory cytokine, that activates either cell survival (e.g.,inflammation, proliferation) or cell death upon association with TNF receptor 1 (TNFR1). Stimuli and the cellular context dictate cell fate decisions between survival and death which rely on tightly regulated mechanisms with checkpoints on many levels. The TNFR1 signaling is controlled by the interplay between post-translational modifications such as proteolytic processing by active caspases or ubiquitination/deubiquitination by LUBAC or CYLD ubiquitin-editing complexes. TNFR1-mediated NFkappaB activation leads to the pro-survival transcriptional program that is both anti-apoptotic and highly proinflammatory. The constitutive NFkappaB or AP1 activation may lead to excessive inflammation which has been associated with a variety of aggressive tumor types (Jackson-Bernitsas DG et al. 2007; Zhang JY et al. 2007). Thus, the tight regulation of TNFα:TNFR1 signaling is required to ensure the appropriate cell response to stimuli.