Simple SummaryNF-κB transcription factors are leading modulators of innate immunity. Recent investigations reveal their interplay with energetic metabolism as a central task of many cell functions, such as immune cell activation. Indeed, requiring energy and metabolites, the defense response must be orchestrated with the cell’s need to save metabolic homeostasis. In this review, new insights about NF-κB function and its crosstalk with energetic metabolism in innate immune cells are discussed in order to improve our knowledge of NF-κB signaling and to better address diagnostic and therapeutic approaches for countless inflammatory diseases.AbstractThe nuclear factor kappa B (NF-κB) is a family of transcription factors that, beyond their numberless functions in various cell processes, play a pivotal role in regulating immune cell activation. Two main pathways—canonical and non-canonical—are responsible for NF-κB activation and heterodimer translocation into the nucleus. A complex crosstalk between NF-κB signaling and metabolism is emerging in innate immunity. Metabolic enzymes and metabolites regulate NF-κB activity in many cases through post-translational modifications such as acetylation and phosphorylation. On the other hand, NF-κB affects immunometabolic pathways, including the citrate pathway, thereby building an intricate network. In this review, the emerging findings about NF-κB function in innate immunity and the interplay between NF-κB and immunometabolism have been discussed. These outcomes allow for a deeper comprehension of the molecular mechanisms underlying NF-κB function in innate immune cells. Moreover, the new insights are important in order to perceive NF-κB signaling as a potential therapeutic target for inflammatory/immune chronic diseases.