Dysregulated inflammatory responses underlie many major diseases, including arthritis, psoriasis, inflammatory bowel disease, atherosclerosis, metabolic disease and cancer. Consequently, there is considerable interest in the pharmaceutical industry in targeting the signaling pathways regulating inflammation as a potential therapeutic approach for treatment of these diseases. Gene expression during inflammatory responses is controlled by NF-kappaB transcription factors, IRF transcription factors and each of the major MAP kinase subtypes (ERK1/2, JNK and p38) in innate immune cells. This symposium will focus on the role of ubiquitination in regulating NF-kappaB and MAP kinase activation, and how NF-kappaB-dependent transcription is coordinated with IRF activation and MAP kinase signaling to control innate immunity. Progress in the therapeutic targeting of NF-kappaB and MAP kinase activation pathways for treatment of chronic inflammatory diseases and cancer will also be discussed.