Immunodeficiency is encountered in children in an array of clinical settings and is most commonly acquired due to either infection (e.g., HIV/AIDS) or immunosuppressive drugs used to treat autoimmune and inflammatory diseases or prevent rejection in children who’ve received solid organ transplantation. Less commonly, immunodeficiency may result from mutations in key genes involved in the regulation of immune cell function and are referred to as primary immunodeficiency disorders. Depending on the underlying mutation, affected children may manifest defects in humoral or cellular immunity or both. Regardless of the underlying cause, children with immunodeficiency have a significantly increased risk of developing a lymphoproliferative disorder (LPD), which range from atypical reactive processes to overtly malignant lymphoma. These include B-cell LPDs and T-/natural killer–cell LPDs far less commonly. The development of LPDs in the setting of immunodeficiency is driven to a large extent by increased susceptibility of affected children to viral infection, primarily by Epstein–Barr virus (EBV), a member of the human herpes virus family. Our discussion includes a review of the primary immunodeficiencies. The central pathogenetic role of EBV in the development of immunodeficiency associated LPDs, including the various latency states of EBV infection, are also reviewed. The focus of this chapter is on the various reactive and malignant LPDs that develop in the setting of immunodeficiency, including the pathologic, immunophenotypic, and genetic features of these disorders, with an emphasis on those LPDs encountered in the pediatric setting. Pediatric hemophagocytic lymphohistiocytosis is also discussed given that it may develop in the context of certain immunodeficient states, particularly in infants and young children. The differential diagnosis of juvenile myelomonocytic leukemia is emphasized throughout our discussion.