Rationale: Insight into the function of nuclear factor (NF)-kB in the adult heart has been hampered by the embryonic lethality of constitutive NF-kB inactivation. Objective: The goal of the present study was therefore to gain insights into the role of NF-kB pathway specifically in mouse cardiomyocytes by conditional deletion of the NF-kB essential modulator (NEMO). Methods and Results: Using a Cre/loxP system, we disrupted the Nemo gene in a cardiomyocyte-specific manner in the heart, which simulated gene expression changes underlying human heart failure and caused adult-onset dilated cardiomyopathy accompanied by inflammation and apoptosis. Pressure overload hallenges of NEMOdeficient young hearts precociously induced the functional decrements that develop spontaneously in older knockout animals. Moreover, oxidative stress in NEMO-deficient cardiomyocytes is a critical pathological component that can be attenuated with antioxidant diet in vivo. Conclusions: These results reveal an essential physiological role for NEMO-mediated signaling in the adult heart to maintain cardiac function in response to age-related or mechanical challenges, in part through modulation of oxidative stress.