The signaling pathways that control the life-death switch of a cell are of primary interest in modern biology. In this respect, NF-??B has emerged as a decisive transcription factor in the cells response to apoptotic challenge and its effects on apoptosis have far-reaching consequences for normal development and/or homeostasis in many cells and tissues, including the immune system, hair follicles, and epidermal appendages, liver, nervous system and recently in heart . In this review we analyze the pivotal role of the transcription factor NF-κB in the normal functioning of the cardiac cell and its implication in common cardiac pathologies, such as ischemia-reperfusion injury, ischemic precondition, hypertrophy, atherosclerosis and cardiac arrest. While NF-κB is usually cytoprotective, it can also be pro-apoptotic depending on the inducing stimulus and the cellular context. Significant progress has been made in elucidating NF-κBs mode of action and its interplay with other key factors. These studies identified some anti- and pro-apoptotic NF-κB regulated genes that mediate its activity. These important new insights fuel hope that novel approaches will be developed to control the effects of NF-κB in cardiac pathologies.