IRF4 is normally expressed in plasma cells, melanocytes, some B-cells, and in activated T-cells. The IRF4 protein is required at several stages of B-cell development, and is also critical for T-cell differentiation. Rearrangements of the IRF4/DUSP22 chromosomal region have been detected in various B-cell and T-cell lymphomas. Large B-cell lymphoma (LBCL) with IRF4 rearrangement, which occurs most commonly in children and young adults, is considered a distinct new provisional entity. These lymphomas most typically occur in Waldeyer ring and/or cervical lymph nodes. Most cases have IG/IRF4 fusions and have a favorable prognosis. Rearrangements of IRF4 and/or DUSP22 have also been described in peripheral T-cell lymphomas and in cutaneous anaplastic large cell lymphoma (ALCL). ALCL is difficult to distinguish from other CD30-positive T-cell lymphoproliferative disorders. IRF4 translocation has a high specificity for cutaneous ALCL supporting the clinical utility of FISH for IRF4 in the differential diagnosis of T-cell lymphoproliferative disorders. Moreover, DUSP22 rearrangement in ALK-negative ALCL is associated with a favorable outcome indicating the usefulness of DUSP22 as a predictive biomarker.