Calpains are a family of Ca2+ dependent cytosolic non-lysosomal proteases with well conserved cysteine-rich domains for enzymatic activity. Due to their functional dependency on Ca2+ concentrations, they are involved in various cellular processes that are regulated by intracellular ca2+ concentration (i.e. embryo development, cell development and migration, maintenance of cellular architecture and structure etc.). Calpains are widely studied proteases in mammalian (i.e. mouse and human) physiology and pathophysiology due to their ubiquitous presence. For example, these proteases have been found to be involved in various inflammatory disorders such as neurodegeneration, cancer, brain and myocardial ischemia and infarction, cataract and muscular dystrophies etc. Besides their role in these sterile inflammatory conditions, calpains have also been shown to regulate a wide range of infectious diseases (i.e. sepsis, tuberculosis, gonorrhoea and bacillary dysentery etc.). One of these regulatory mechanisms mediated by calpains (i.e. calpain 1 and 2) during microbial infections involves the regulation of innate immune response, inflammation and cell death. Thus, the major emphasis of this review is to highlight the importance of calpains in the pathogenesis of various microbial (i.e. bacterial, fungal and viral) diseases and the use of calpain modulators as potential immunomodulators in microbial infections.