Mast cells are enigmatic cells that are recognized as critical components of our immune system. They are strategically localized at the host/environment interface, display a long lifespan once situated in tissues and have the ability to produce, store and upon activation, release immuno-regulatory molecules. In specific acute and chronic conditions, mast cell accumulation, activation and release of mediators are important for the initiation and perpetuation of the inflammation associated with these disease states. During the past decade, regulatory pathways for mast cell survival have been elucidated, which have, in part, helped to explain the increased number and survival of mast cells observed during inflammatory reactions associated with, e.g., the allergic response. One key group of regulators involved in cell survival and apoptosis is the Bcl-2 family of proteins. The Bcl-2 family consists of pro- and anti-apoptotic members, where the balance between these members determines cellular fate via protein-protein interactions. In this chapter, we will discuss the regulation of mast cell apoptosis and survival and how understanding the mechanisms by which Bcl-2 family members regulate mast cell survival could lead to the identification of key proteins that affect the severity of inflammation. This knowledge could be used to develop treatments for mast cell disorders such as mastocytosis and other inflammatory diseases where mast cells are involved.