The multiple cell types that comprise the immune system provide an efficient defense system against invading pathogens and micro-organisms. In general, immune cells are activated for disparate functions, such as proliferation, production and release of mediators and chemotaxis, as a result of interactions between ligands and their matching immunoreceptors. This in turn leads to the recruitment and activation of a cascade of second messengers, via their regulators/adaptors, that determine the net effect of the initial response. However, activation of cells of the immune system must be tightly regulated by a finely tuned interplay between activation and inhibition to avoid excessive or inappropriate responsiveness and to maintain homeostasis. Loss of inhibitory signals may disrupt this balance, leading to various pathological processes such as allergic and auto-immune diseases. In this chapter, we will discuss down-regulating mechanisms of mast cells focusing on immunoreceptor tyrosine-based inhibition motifs (ITIM)-containing inhibitory receptors (IR).