Many proteins first identified in the immune system are also expressed in the developing and adult nervous system. Unexpectedly, recent studies reveal that a number of these proteins, in addition to their immunological roles, are essential for the establishment, function, and modification of synaptic connections. These include proinflammatory cytokines (e.g., TNFα, IL-6), proteins of the innate immune system (e.g., complement C1q and C3, pentraxins, Dscam), members of the major histocompatibility complex class I (MHCI) family, and MHCI-binding immunoreceptors and their components (e.g., PIRB, Ly49, DAP12, CD3ζ). Understanding how these proteins function in neurons will clarify the molecular basis of fundamental events in brain development and plasticity and may add a new dimension to our understanding of neural-immune interactions in health and disease.