FAS-associated factor 1, FAF1, is an evolutionarily conserved protein that has several protein interaction domains. Although FAF1 was initially identified as a member of the FAS death-inducing signaling complex, subsequent work has revealed that FAF1 functions in diverse biological processes. FAF1 has been shown to play an important role in normal development and neuronal cell survival, whereas FAF1 downregulation may contribute to multiple aspects of tumorigenesis. In particular, there is compelling evidence implicating FAF1 as a tumor suppressor involved in the regulation of apoptosis and NFkappaB activity, as well as in ubiquitination and proteasomal degradation. Here, we highlight FAF1's role in NFkappaB signaling and postulate that this pathway has critical connotations for the pathogenesis and treatment of human cancers.