Mast cells (MCs) help regulate inflammatory processes in all human tissues, especially at environmental interfaces and perivascular sites. MC activation leads to release of various inflammatory mediators. Aberrant MC mediator release is the defining characteristic of MC activation syndrome (MCAS), a recently recognized heterogeneous group of disorders characterized by chronic, multisystem inflammation with or without allergy and for which no efficient treatment strategies exist. Recent research, not yet independently confirmed, suggests most MCAS cases bear mutations in KIT, the MC regulatory gene (MCRG) dominantly controlling MC activation. Other MCRGs, too, may be mutated in MCAS, suggesting different MCRG mutational profiles drive different variants of MCAS. These researchers seek to confirm the commonness of heterogeneous KIT mutations (and to newly identify other MCRG mutations) in MCAS to set the stage for a new paradigm of exploration of clonal MCAS variants as root causes of heretofore idiopathic epidemic chronic inflammatory diseases (e.g., fibromyalgia, chronic fatigue).