Immune tolerance is a highly regulated state and involves diverse mechanisms. Central to the induction of tolerance is the targeted modulation of T-cell activities (both effector and regulatory), in which transcription factors play a significant role. The nuclear factor kappa-B (NF-κB) family is a family of transcription factors that not only are critically involved in diverse T-cell responses but also are regulated by many mechanisms to maintain tolerance and T-cell homeostasis. NF-κB, as a transcription factor, has been extensively studied in recent decades, and the molecular mechanisms that regulate NF-κB activities have been well documented. However, recent studies have revealed exciting new roles for NF-κB; in addition to its transcriptional activity, NF-κB can also activate diverse epigenetic mechanisms that mediate extensive chromatin remodeling of target genes to regulate T-cell activities. In this review article, we highlight recent discoveries and emerging opportunities in targeting NF-κB family members as well as their associated chromatin modifiers in the induction of immune tolerance and in the clinical treatment of immune diseases.