Mast cells are tissue-localized cells that play an important role in immunity and inflammation. Following an offensive event they act as cellular sensors that via the activation of cell surface receptors launch a cellular response culminating in the release of a whole set of inflammatory mediators and products. This response is initially destined to restore tissue homeostasis, but in case of chronic injury or deregulation also promotes pathology. To further understand the action of mast cells in their environmental context it is necessary to decipher the molecular mechanisms of their activation as well as the ensuing cellular responses. This will allow identification of new strategies to promote their beneficial actions or, at the contrary, to interfere with their pathological consequences. While in the past many studies have focused on responses engaged by high affinity IgE receptor because of its implication in the allergic response, it has become clear that mast cells can be activated by multiple types of receptors initiating an intense molecular crosstalk between receptors and signaling pathways that can either synergize, antagonize and in some cases produce new types of responses. Mast cells can indeed react with an astounding diverse array of cellular responses that sometimes are engaged selectively. This Research Topic will focus on selected articles that shed some new light on the molecular mechanisms of mast cell activation, the possible crosstalk between signaling pathways and the ensuing cellular responses that allow mast cells to act as cellular sensors in tissues.