Mast cells (MC) are found perivascularly in all tissues and may function as the sentinel immune cells sensing danger and then acting as the master conductor to orchestrate responses aimed at restoring homeostasis. Yet, MC are best known for their critical role in allergic, but also inflammatory and other neuroimmune conditions. MC are stimulated by allergens, but also by many other environmental, neuroimmune, pathogenic and stress triggers. Stimulation of MC is called “activation” and is associated with the release of numerous neurohormonal, proinflammatory, tissue remodeling and vasoactive mediators via different secretory mechanisms, some of which do not involve the release of histamine and tryptase. However, mast cell activation and the subsequent responses may become excessive either because of persistent stimulation or dysregulation. Clinical and experimental evidence indicates that MC may be regulated by innate molecules, some derived from MC, themselves. However, discovery of such innate, natural, inhibitors has not been a priority even though they would substantially change the treatment of mast cell activation disorders (MCADs) since drugs that are available or under development focus on inducing MC apoptosis. Development of effective inhibitors of MC activation would require access to MC from healthy and MCAD subjects, preferably identical twins, that would allow differential investigation of the respective transcriptome.