Mast cells are ancient sentinel immune cells that emerged more than 500 million years ago and predate the development of the adaptive immune system. In humans, these cells are located at mucosal surfaces and surrounding blood vessels and nerves, making them uniquely situated to regulate the function of the vasculature, to initiate the recruitment and activation of leukocytes into tissues, and to trigger physiological responses that are mediated by the nervous system. Mast cells are important regulators of innate immune responses, and they orchestrate protective adaptive inflammatory responses to combat infection and initiate wound healing. Mast cells are also responsible for acute inflammatory responses, resulting in bronchoconstriction and edema and are important in the evolution of allergic late phase responses, contributing to the pathogenesis of chronic allergic diseases such as asthma, atopic dermatitis, and rhinitis. In this context, mast cells are an attractive therapeutic target. Recently, modern biotechnologies and nanotechnologies have emerged that may shed some light on the function and biology of these important cells. Bioengineering strategies are using complex protein structures to trigger or inhibit specific mast cell receptors. Polymeric and lipid nanostructures and nanoparticles can be used to alter mast cell functionality, and complex machine learning and in silico modeling can be used to unlock novel molecular interactions on the mast cell surface and within its complex intracellular structures. In these ways, our understanding of these ancient cells is growing.