Mast cells (MCs) are among the first cell types associated with allergies and asthma. Studies in human asthma have identified their presence in the lung submucosa and smooth muscle and also in the airway epithelium. As our understanding of the distribution and location of these MCs in the human airway has increased, it is clear that much remains to be understood regarding the presence and subtype of these MCs in relationship to asthma phenotypes, defined both clinically and on the basis of immunologic pathways. Human MCs have traditionally been divided into two major subtypes based on the protease granule content, with tryptase representing total MCs. There is emerging evidence that in the epithelium, MCs of an altered subtype (with tryptase, chymase, and/or carboxypeptidase A3) may play a role in the pathophysiology of poorly controlled, severe, Th2-associated asthma.