Mast cells (MCs), which are granulated tissue-resident cells of hematopoietic lineage, constitute a major sensory arm of the innate immune system. In this review we discuss the evidence supporting the dual role of MCs, both as sentinels for invading pathogens and as regulatory cells throughout the course of acute inflammation, from its initiation to resolution. This versatility is dependent on the ability of MCs to detect pathogens and danger signals and release a unique panel of mediators to promote pathogen-specific clearance mechanisms, such as through cellular recruitment or vascular permeability. It is increasingly understood that MCs also contribute to the regulated contraction of immune activation that occurs within tissues as inflammation resolves. This overarching regulatory control over innate immune processes has made MCs successful targets to purposefully enhance or, alternatively, suppress MC responses in multiple therapeutic contexts.