This chapter focuses on the crosstalk between the central nervous system (CNS) and the peripheral immune system, with particular emphasis on the role of the complement system. The chapter traces the evolution of brain-periphery interactions from development through adulthood and into pathological states. During early development, brain structures such as the vasculature engage in critical communication with blood-borne elements to shape resident myeloid populations in the CNS. This interaction is reduced during adulthood, due to the blood-brain barrier (BBB) and other CNS limitans, which restrict immune cell access to the brain under normal conditions. However, damage to these barriers can disrupt the controlled environment, making brain-periphery crosstalk a crucial factor in the pathophysiology of various CNS diseases. The chapter highlights the cerebral vasculature as a primary interface for this interaction, particularly in the context of ischemic stroke. Ischemic stroke, characterized by a blockage of blood supply to the brain, exemplifies how systemic inflammation can elevate stroke risk and, conversely, how stroke can activate systemic inflammatory pathways. The complement system is central to this bidirectional communication, mediating neuroinflammation and influencing disease outcomes. Through a detailed exploration of these processes, the chapter underscores the significance of complement-mediated neuroinflammation in brain-periphery interactions, its implications for cerebrovascular diseases, and its potential as a therapeutic target.