The brain is both the orchestrator as well as the target of the innate immune system's response to the aseptic trauma of surgery. When trauma-induced inflammation is not appropriately regulated persistent neuro-inflammation interferes with the synaptic plasticity that underlies the learning and memory aspects of cognition. The complications that ensue, include postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) at two poles of a constellation that is now termed perioperative neurocognitive disorders. While the relationship of acute POD to the more indolent POCD is not completely understood both can be further complicated by earlier-onset of dementia and higher mortality. How and why these disorders occur is the focus of this report. The innate immune system response to peripheral trauma signals to the brain through a regulated cascade of cellular and molecular actors producing a teleological defense mechanism, “sickness behavior,” to curtail further injury and initiate repair. Sickness behavior, including disordered cognition, is terminated by neural and humoral pathways that restore homeostasis and launch the organism on a path to good health. With so many “moving parts” the innate immune system is vulnerable in clinical settings that include advanced age and lifestyle-induced diseases such as “unhealthy” obesity and the inevitable insulin resistance. Under these conditions, inflammation may become exaggerated and long-lived. Consideration is provided how to identify the high-risk surgical patient and both pharmacological (including biological compounds) and non-pharmacological strategies to customize care.