There is convincing evidence that inflammation plays a pivotal role in the pathophysiology of complex regional pain syndrome (CRPS). Besides inflammation, central sensitization is also an important phenomenon. Mast cells are known to be involved in the inflammatory process of CRPS and also play a role (at least partially) in the process of central sensitization. In the development of a more mechanism-based treatment, influencing the activity of mast cells might be important in the treatment of CRPS. We describe the rationale for using medication that counteracts the effects of mast cells in the treatment of CRPS.