OBJECTIVE Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is an uncommon large B-cell neoplasm recognized by the World Health Organization as a distinct entity on the basis of its unique clinical features, histogenesis, phenotype, and pathogenetic mechanisms. The diagnosis of PMBL can be challenging because of features that may overlap with other (Hodgkin and non-Hodgkin) lymphoma types. This review describes our approach to the diagnosis of PMBL. METHODS Two cases are presented to illustrate how we diagnose PMBL and separate PMBL from related histologic and biological mimickers, such as Hodgkin lymphoma and gray zone lymphoma. RESULTS A diagnosis of PMBL requires correlation of morphology and immunophenotype with clinical and staging data. Gene expression analysis is not typically performed in clinical labs but has expanded our understanding of the functional pathways underlying this disease and helped identify biomarkers that can be translated to diagnostic practice and possibly to future therapeutic options. CONCLUSIONS PMBL and closely related entities can pose diagnostic challenges. It is important to understand the borders between PMBL and other closely related lymphoma types so that patients receive successful primary treatment with curative intent.