Inflammatory activation of NF-kappaB involves the stimulus-induced degradation of the NF-kappaB-bound inhibitor IkappaB via the IkappaB kinase (IKK). In response to UV irradiation, however, the mechanism and function of NF-kappaB activation remain unclear. Using a combined biochemical, genetic, and computational modeling approach, we delineate a dual requirement for constitutive IKK-dependent and IKK-independent IkappaB degradation pathways in conjunction with UV-induced translational inhibition. Interestingly, we find that the high homeostatic turnover of IkappaB in resting cells renders the NF-kappaB system remarkably resistant to metabolic stresses, but the two degradation pathways critically and differentially tune NF-kappaB responsiveness to UV. Indeed, in the context of low chronic inflammation that accelerates NF-kappaB-bound IkappaB degradation, UV irradiation results in dramatic NF-kappaB activation. Our work suggests that the human health relevance of NF-kappaB activation by UV lies with cellular homeostatic states that are associated with pathology rather than with healthy physiology.