The limitation of light microscopy in the study of mast cells prompted the employment of other imaging platforms. A platform that was widely used in the early sixties through mid-eighties was electron microscopy. Using the RCA EMU-2A electron microscope, \citet{Smith_1957} studied mast cells isolated – via centrifugation – from the peritoneal fluid of adult male rodents. The cells were dehydrated with various alcohol concentrations before they were embedded in plastic and gelatin and cut into thin sections prior to imaging. The authors noted the subpar quality of the electron micrographs in preserving the structural integrity of the mast cells. However, the authors stressed that the mast cells that they obtained appeared similar to those isolated from skin, spleen, and liver that were prepared according to the method developed by \cite{14927794}.   The morphology of normal mast cells was described as having a large nucleus occupied by thread-like structures with empty spaces towards the interior, multiple round or oval-like electron-dense bodies with a diameter of 0.5-1.0 µ (Smith 1957). Thread-like materials that resemble those in the nucleus were present inside these electron-dense structures (cytoplasmic granules), albeit they were thinner with fine granule-like particles attached to them.  In addition to imaging normal mast cells, the effects of total body irradiation and intraperitoneal (IP) injection of heparin-binding agent – toluidine blue and protamine sulfate – and histamine-releasing agent, stilbamidine were investigated. The size of the granules and the inner structures remained unchanged in mast cells isolated from IP-injected rats. However, each granule seemed to be surrounded by a halo of clear cytoplasm enclosed and separated from each other by the perigranular membrane. Unlike the untreated and IP-injected mast cells, cells isolated from irradiated rodents had more electron-dense bodies that were much larger than the typical size range of a secretory granule with fewer inner reticular structures. The nucleus appeared elongated and deformed and together with the lack of intragranular structures, mirrored that observed under the light microscope, which is suggestive of cells undergoing apoptosis (Smith, 1957).  
The plasma membrane of rat peritoneal mast cells was reported to exhibit finger-like projections that protrude into the extracellular space  (Lagunoff, 1972). This structural component was also observed in rat mast cells in the tongue (Enerb�ck et al., 1974). However, this microvillus-like folding of the membrane was absent in mast cells observed in the lamina propria of the gut mucosa. In addition to the smooth cell membrane, mucosal mast cells often exhibited irregularly-shaped nuclei with indentations (Enerb�ck et al., 1974) with fewer but larger granules as compared to tongue mast cells, which contained numerous and fairly-uniform sized granules that were within the size range reported by Smith (1957). The intragranular structures in tongue mast cells exhibited a homogeneous fine particulate appearance whereas those in mucosal mast cells were composed of coarse particles. Besides this, other mesenchymal and granular (mainly eosinophils) cell types as well as phagocytic immune cells, were typically found in contact or in close proximity to mucosal mast cells  (Enerb�ck et al., 1974). They also appeared smaller than peritoneal mast cells and were often found localised near nerves and blood vessels  (Lagunoff, 1972).
 The morphology of human mast cells under normal/untreated conditions was explored using electron microscopy. Tissue biopsies were obtained from digital and abdominal skin and subcutis, as well as the gastric mucosa  Hibbs et al. (1960). The samples were divided for imaging by light and electron microscopy where the tissue specimens were processed as described by Smith (1957). Two morphologically distinct cells were observed: One was spindle-shaped with an elongated nucleus and numerous tightly-packed granules wherein the internal structures were not visually apparent; the other type was round or ovoid with many cytoplasmic granules that were more widely distributed. Unlike the light microscope, at the highest magnification of X50 000 of the objective lens of the electron microscope, the authors were able to observe the intragranular structures in the ovoid cells. They appeared to consist of two components – fine particles and lamellar/scroll-like structures. Variations exist between cells with regard to the composition and localisation of these components such that the granules may be composed of mostly fine particles or lamellar or a mix of both. Similar to the skin and dermis, both cell types were observed in the gastric mucosa specimen. However, only the ovoid cells were found in the specimen obtained from a patient who received intensive adrenocorticosteroid treatment. Furthermore, only the lamellar structure within the granules could be observed; the other component was rarely found in these cells, which lead the authors to the hypothesis that the steroid treatment caused the fine particles to be released from the granules. The study also highlighted another advantage of electron microscopy – it enabled the identification of two cell types as distinct cells, which was not feasible via the light microscope  (Hibbs et al., 1960).
Electron microscopic studies of mast cells have been done with ultra-thin sections of tissue specimens and liquid samples from various tissues and mammals.  Smith (2006) compiled a list of studies highlighting the source of mast cells that were utilised to-date and noted that the cells had undergone similar processes prior to imaging, that is, the cells were fixed with osmium tetroxide and methacrylate, followed by embedding in plastic/Epon resin, and stained with uranyl acetate. Micrographs from these individual studies of normal mast cells appeared similar across species (Smith 2006). The separation between granules by a two-layer electron-dense structure was evident in untreated mast cells, although in certain cells, many granules were was only partially surrounded by this perigranular membrane (Lagunoff 1972). The variability in the intragranular structures observed by Hibbs et al. (1960) was evident across different mast cell types of different mammal species.