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Mast cells (MCs) are versatile immune cells capable of rapidly responding to a diverse range of extracellular cues. Here, we mapped the genomic and transcriptomic changes in human MCs upon diverse stimuli. Our analyses revealed broad H3K4me3 domains and enhancers associated with activation. Notably, the rise of intracellular calcium concentration upon immunoglobulin E (IgE)-mediated crosslinking of the high-affinity IgE receptor (FcεRI) resulted in genome-wide reorganization of the chromatin landscape and was associated with a specific chromatin signature, which we term Ca2+-dependent open chromatin (COC) domains. Examination of differentially expressed genes revealed potential effectors of MC function, and we provide evidence for fibrinogen-like protein 2 (FGL2) as an MC mediator with potential relevance in chronic spontaneous urticaria. Disease-associated single-nucleotide polymorphisms mapped onto cis -regulatory regions of human MCs suggest that MC function may impact a broad range of pathologies. The datasets presented here constitute a resource for the further study of MC function. • Enhancers and broad H3K4me3 domains are enriched in genes regulating MC functions • Intracellular calcium levels govern the chromatin landscape upon FcεRI crosslinking • Disease-associated SNPs are enriched in regulatory chromatin regions of human MCs Cildir et al. map the genomic and transcriptomic changes in human mast cells upon diverse stimuli, defining chromatin changes associated with activation and Ca2+ flux and revealing potential effectors of mast cell function. Disease-associated SNPs mapped onto cis -regulatory regions of mast cells suggest that mast cell function may impact a broad range of pathologies. [ABSTRACT FROM AUTHOR]