The Nuclear Factor-kappaB (NF-kappaB) signaling pathway has been linked to several pathologic processes in the myocardium including cardiomyocyte proinflammatory cytokine release, ischemia/reperfusion injury, hypertrophy and apoptosis. However, very little is known about the intracellular mechanisms that govern NF-kappaB activity in the myocardial cells. Recent advances in our understanding of the regulation of NF-kappaB signaling in non-myocyte systems suggest that the activity of the NF-kappaB pathway is tightly regulated by a diversity of stress-activated signaling intermediates through direct post-translational modification of various components of the NF-kappaB pathway. In this review, we will focus on these recent revelations and their implications not only in cardiac pathologies, but in the development of new therapeutic strategies to manage heart disease.