Mast cells (MCs) were first described by Paul Ehrlich as well fed granular cells that stain metachromatically. Today MCs are regarded as multifunctional, granulated, tissue-dwelling cells distributed in the perivascular spaces and connective tissues of every major organ of the body. Their long recognized phenotypic diversity might be associated not only with their anatomic distribution and mediator repertoire, but also with their functional characteristics related to the regulation of effector pathways. In addition to their historical involvement in type I hypersensitivity response, MCs have emerged as versatile effector cells with functional diversity and homeostatic functions in non-IgE-mediated inflammatory responses, autoimmunity, bidirectional interactions with the neuroendocrine circuit, the urinary, gastrointestinal, cardiovascular and endocrine systems, in metabolism and malignancy. Thus, MCs appear to receive, integrate and transmit a wide range of signals in their microenvironment, coordinated by the differential release of their pro-inflammatory and anti-inflammatory granular mediators. Understanding the heterogeneity of this complex cellular communication may provide a tool for selective pharmacological intervention directed to specific MC subsets.