Plasmablastic lymphoma and plasmablastic myeloma are similar in morphology. Tumor substrate in both is characterized by large cells with blastic morphology, central or somewhat eccentric nuclei, large central nucleolus or some distinct nucleoli, and abundant eosinophilic cytoplasm. The common characteristic of both B-cell tumors is the expression of plasma cell differentiation markers (CD38, CD138, MUM-1/IRF-4, interferon regulatory factor 4, PRDM-1, PR domain zinc finger protein 1, and/or XBP-1, X-box-1 binding protein) with a frequent loss of CD20. These rare nosological entities with similar morphological and immunohistochemical features present a challenge for differential and reliable diagnosis. The present review deals with clinical signs, diagnostically significant immunohistochemical markers, and molecular genetic characteristics which are essential for differential diagnosis of plasmablastic lymphoma and plasmablastic myeloma.