Antimicrobial peptides (AMPs) are ancient and essential elements of the host defense system, which are found in a wide variety of species. They show antimicrobial activity against a wide range of pathogenic microorganisms. In addition, AMPs are expressed by different immune cells and have a important function in host innate immune response against pathogens by mechanisms that are different from those involved in direct microbial cytolysis. One host innate immune response that is directly activated by AMPs involves induction of localized inflammation through interaction with mast cells. Activation of mast cells releases pre-formed mediators, cytokines, chemokines and eicosaniods, which influence recruitment, survival, phenotype and functions of many immune cells. Mast cells can respond to AMPs independent of antigen and Fc epsilon receptor 1 stimulation. One of these pathways involves G protein-coupled receptor signaling, which can lead to mast cell degranulation. Whether AMPs activate G proteins in mast cells through a receptor-dependent or a receptor-independent mechanism remains poorly understood and there are a great many questions that have yet to be answered. In this review, we will discuss the possible involvement and role of GPCRs in mast cells activation by AMPs and the gaps in our current understanding of this important interaction.