The inactive transcription factor NF-κB is localized n the cytoplasm and rapidly responds to a variety of extracellular factors and intracellular stress conditions to initiate multiple cellular responses. While the knowledge regarding NF-κB signaling pathways initiated by extracellular ligands is rapidly expanding, the mechanisms of activation by intracellular stress conditions are not well understood. We recently described a critical role for a small ubiquitin-like modifier (SUMO) modification of NF-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase, in response to cretain genotoxic stress conditions. One important unanswered question is whether the role of this modification is limited to the genotoxic agents or some other signaling pathways also employ SUMOylation of NEMO to regulate NF-κB activation. Here, we report that a variety of other stress conditions, including oxidative stress, ethanol exposure, heat shock and electric shock also induce NEMO SUMOylation, thus demonstrating that DNA damage per se is not necessary for this NEMO modification to occur. Moreover, combinations of certain SUMO stress and ATM (ataxia telangiectasia mutated) activation conditions lead to NF-κB activation without inducing DNA damage. Our study helps to conceptualize how individual or a combination of different stress conditions may funnel into this previously unappreciated signal transduction mechanism to regulate the activity of the ubiquitous NF-κB transcription factor.