Inflammatory mediators of trauma and sepsis transduce cellular events through cell surface receptors initiating intricate membrane and cytosolic reaction cascades that funnel through surprisingly few checkpoints in order to provoke a cellular response. As critical care surgeons, we can explore these cell signalling systems. The purpose of this article is to delineate the six known second messenger pathways relevant to surgical sepsis and trauma. Our comprehension of these signaling systems may offer us an opportunity to blunt post-traumatic cellular injury and promote a constructive response.