This review article is an attempt to trace the evolution of mast cells (MCs). These immune cells have been identified in all vertebrate classes as single-lobed cells containing variable amounts of membrane-bound secretory granules which store a large series of mediators, namely histamine, proteases, cytokines and growth factors. Other MC features, at least in mammals, are the c-kit receptor for the stem cell factor and the high-affinity receptor, FcεRI, for immunoglobulin E (IgE). The c-kit receptor also has been identified in fish MCs. The FcεRI receptor seems to be a more recent acquisition in MC phylogenesis given that IgE originated in mammalian species. Tryptase and histamine have also been recognized in MCs of teleost fish. Thus, a cell population with the overall characteristics of higher vertebrate MCs is identifiable in the most evolutionarily advanced fish species. Two potential MC progenitors have been identified in ascidians (urochordates which appeared approximately 500 million years ago): the basophil/MC-like granular haemocyte and the test cell. Both contain histamine and heparin, and provide defensive functions. Some granular haemocytes in Arthropoda also closely approximate the ultrastructure of modern MCs. The origin of MCs is probably to be found in a leukocyte ancestor operating in the context of a primitive local innate immunity and involved in phagocytic and killing activity against pathogens. From this type of defensive cell, the MC phylogenetic progenitor evolved into a tissue regulatory and remodelling cell, which was incorporated into the networks of recombinase activating genes (RAG)-mediated adaptive immunity in the Cambrian era, some 550 million years ago. Early MCs probably appeared in the last common ancestor we shared with hagfish, lamprey and sharks about 450-500 million years ago.