Both cellular and humoral functions of the immune system are modulated by the sympathetic nervous system (SNS). This interaction is mainly mediated by the release of catecholamines (CA) and their receptor-specific action on immune cells. However, neuropeptide Y (NPY), also present in sympathetic nerve terminals, is released upon SNS-stimulation. NPY modulates potent immunological effects in vitro and in vivo, such as differentiation of T helper cells, monocyte mediator release, NK cell activation, and immune cell redistribution. In addition to this direct action within the neuroimmune crosstalk, NPY is also able to modulate the immunomodulatory effects of other neurotransmitters, thereby acting as a neuroimmune co-transmitter. This review will discuss key findings from recent studies, provide implications for the clinical situation, and integrate the pleiotropic functions of NPY in the context of neuroimmune interactions.