The inflammatory response plays an important role in host defense and maintenance of homeostasis, while imbalances in these responses can also lead to pathologic disease processes. Emerging data show that RKIP interacts with multiple signaling molecules that may potentiate multiple functions during inflammatory processes. Here, we review the interaction of RKIP with both the MAPK and NF-κB pathways in relation to chronic inflammatory diseases. In these settings, it can both inhibit inflammatory pathways as well contribute to pro-inflammatory signaling, often depending on the interactions with multiple proteins and perhaps lipids. The interactions of RKIP with proteins, phospholipids, fatty acids, and their enzymes thus could play a substantial role in diseases like asthma and diabetes. Targeting interactions of RKIP with these pathways could lead to novel approaches to treatment.