Controversies exist in literature regarding nature, pathogenesis, and behaviour of giant cell lesions (GCLs) of jaws. Studies were attempted to solve these mysteries with immunohistochemical analysis, using various biological markers. Thus, the aim of this review is to appraise the role of immunohistochemistry (IHC) in evaluating the pathogenesis, cellular phenotype, nature, and behaviour of GCLs of jaws. PubMed, PubMed Central, and Clinical Key (Medline) databases were searched electronically irrespective of date of publication with assortment of several independent terms. Fifty-five articles that fulfilled the eligibility criteria were included in the review. Out of 55 included articles, 49 were associated with nature, pathogenesis, and behaviour and six articles were associated with treatment and outcome prediction. Although IHC solved some of the controversies associated with GCLs of jaws such as the osteoclastic phenotype of multinucleated giant cells, immunoexpression of proliferative markers does not distinct non-aggressive from aggressive central GCL but the nature, histogenesis, pathogenesis, and exact behaviour still remain debatable. With regard to formulation of treatment plan, immunohistochemical analysis revealed that expression of glucocorticoid and calcitonin receptors could act as a tool to decide the therapeutic strategy and aid in therapeutic adjustments according to evolution of the lesion.