Primary effusion lymphoma (PEL) is a rare and aggressive disease, affecting a unique population of patients who are often elderly or immunocompromised. PEL is associated with human herpesvirus type-8 infection and most commonly presents as malignant effusions of the body cavities. Patients diagnosed with PEL often have a compromised immune system from secondary conditions such as HIV. Chemotherapy has traditionally been the cornerstone of treatment for patients with a good performance status and no significant comorbidities. However, an optimal regimen does not exist. Most patients with PEL experience a relapse after frontline therapy within 6-8 months and subsequently require further treatment. In recent years, our understanding of the molecular drivers and environmental factors affecting the pathogenesis of PEL has expanded. This review will discuss the pathogenesis of PEL and various management approaches available in the frontline and relapsed setting as well as targeted agents that have shown promise in this disease.