The mast cells are multi-effector cells with wide distribution in the different body parts and traditionally their role has been well-defined in the development of IgE-mediated hypersensitivity reactions including bronchial asthma. Due to the availability of genetically modified mast cell-deficient mice, the broadened pathophysiological role of mast cells in diverse diseases has been revealed. Mast cells exert different physiological and pathophysiological roles by secreting their granular contents, including vasoactive amines, cytokines and chemokines, and various proteases, including tryptase and chymase. Furthermore, mast cells also synthesize plasma membrane-derived lipid mediators, including prostaglandins and leukotrienes, to produce diverse biological actions. The present review discusses the pathophysiological role of mast cells in different diseases, including atherosclerosis, pulmonary hypertension, ischemia-reperfusion injury, male infertility, autoimmune disorders such as rheumatoid arthritis and multiple sclerosis, bladder pain syndrome (interstitial cystitis), anxiety, Alzheimer's disease, nociception, obesity and diabetes mellitus.