Mast cells (MCs) are principal effector cells of type-I-allergic reactions but still poorly defined in humans. The consortium Functional Annotation of the Mammalian Genome 5 has created a map of body-wide transcriptome data for a multitude of human cell types, including MCs. MCs were found to have a surprising transcriptional landscape expressing a range of genes not (or barely active) elsewhere in the body. Whereas several MC specific genes have no annotated function, others belong to networks defining specific MC traits and functions, such as granule architecture, IgER signaling, exocytosis and mediator production. Several of these genes are so highly enriched in MCs (versus all other cells), that they appear potentially specific targets for therapeutic interventions in diseases in which MCs are actively involved. We present some interesting candidates, highlight the uniqueness of MCs and discuss their role in allergy and itch sensation based on these renewed insights.