Mast cells, components of the immune system, promote allergic symptoms such as itching, sneezing, and increased intestinal motility. Although mast cells have a detrimental role in allergies, they might have unrecognized physiological functions. Indeed, mast cells have been reported to protect against lethal envenomation. I hypothesized that mast cells have a protective role in the defense against toxins. Because toxin-induced diarrheal diseases are one of the top five causes of mortality in children worldwide (induced by cholera toxin, for example), I tested the role of mast cells in sensing relevant dietary toxins. My goals were to a) establish an in vitro model of mast cell activation using foodborne toxins and b) determine the mast cell transcriptional programs induced by these toxins. To establish the in vitro model, I generated mast cells from murine bone marrow precursors and cultured them in mast cell-specific media for 5 weeks. Mature mast cells were then stimulated with toxins from phylogenetically distinct origins. I found that, surprisingly, no toxin was able to induce significant cell death, even after 24h of culturing, suggesting that mast cells are resistant to the toxic effects of these compounds. To assess mast cell activation, I quantified the levels of TNF-α 6h after toxin exposure. None of the toxins were able to induce TNF-α production by mast cells, suggesting that toxins might not induce inflammation in mast cells. However, I found that mast cells induced expression of activation-related transcripts like Il1b, Tpsab1, Alox5, Egr1, Tnfa and Hdc in response to cholera toxin, when compared with controls. Mast cells stimulated with retrorsine induced the expression of Tph1, Alox5, Il1b and Hdc. Deoxynivalenol induced Ltc4, Il6, Tpsab1, Tnfa, Hdc, and Alox5 while okadaic acid induced Il6, Tnfa, Tph1, Alox5, Egr1, Il1b and Hdc expression. Aconitine only induced Il6, Hdc, and Tpsab1. Lastly, Ochratoxin A induced expression of Il1b, Il6, Tpsab1, Egr1 and Hdc. Altogether, these results suggest that mast cells directly sense and respond to food toxins, which was unknown. How exactly mast cells contribute to toxin defenses will be crucial to investigate as they impact both toxin-induced and inflammatory diseases.