A major aspect of the regulatory function of mast cells appears to be their role as intermediaries between the nervous and immune systems. Mast cells are activated by neurotransmitters allowing neural control of innate and adaptive immunity. Conversely, mast cells secrete mediators including neurotransmitters and neurotrophic factors that directly influence nerves, causing acute activation and/or long-lasting changes in excitability and phenotype. While some basic mechanisms underlying mast cell-nerve communication are well-established, the full extent to which this relationship influences health and disease is unclear. Future studies of mast cell-nerve interactions may provide greater understanding of how immune and nervous systems coordinate multiple aspects of homeostatic control, and will potentially offer therapeutic targets in both immune and neurological disorders.