Hepatosplenic T-cell lymphoma (HSTCL) is a rare T-cell neoplasm that most commonly arises from a small subset of γ/δ T-cell receptor-expressing lymphocytes. HSTCL is more common in adolescent and young adults and has a rapidly progressive clinical course and poor outcome due to its refractoriness to conventional chemotherapy regimens. Approximately 20% of the cases arise in the background of chronic immunosuppression or immune dysregulation. Patients commonly present with constitutional symptoms, hepatic and liver enlargement, and cytopenias; hematophagocytic syndrome can also occur. The most frequent chromosomal aberrations associated with HSTCL are isochromosome 7q and trisomy 8, and most cases harbor mutations in genes involved in chromatin modification or the JAK/STAT pathway. The rarity of this disease, along with lack of nodal involvement and presenting symptoms that mimic different entities including infectious etiologies, makes this lymphoma a significant diagnostic challenge. In this review, we highlight the clinical and pathologic features of HSTCL. Moreover, we summarize the results of recent molecular studies suggesting potential targets for novel therapeutics strategies.