Inflammation is the mechanism of diseases caused by microbial, autoimmune, allergic, metabolic, and physical insults that produce distinct types of inflammatory responses. This etiologic view of inflammation informs its classification based on a cause-dependent mechanism as well as a cause-directed therapy and prevention. The genomic era ushered in a new understanding of inflammation by highlighting the cell's nucleus as the center of the inflammatory response. Exogenous or endogenous inflammatory insults evoke genomic responses in immune and non-immune cells. These genomic responses depend on transcription factors, which switch on and off a myriad of inflammatory genes through their regulatory networks. We discuss the transcriptional paradigm of inflammation based on denying transcription factors' access to the nucleus. We present two approaches that control proinflammatory signaling to the nucleus. The first approach constitutes a novel intracellular protein therapy with bioengineered physiologic suppressors of cytokine signaling. The second approach entails control of proinflammatory transcriptional cascades by targeting nuclear transport with a cell-penetrating peptide that inhibits the expression of 23 out of the 26 mediators of inflammation along with the 9 genes required for metabolic responses. We compare these emerging anti-inflammatory countermeasures to current therapies. The transcriptional paradigm of inflammation offers nucleocentric strategies for microbial, autoimmune, metabolic, physical, and other types of inflammation afflicting millions of people worldwide. This article is protected by copyright. All rights reserved.