Pain is a subjective symptom whose prevalence can be grossly underestimated. The high proportion of adults with thalassemia who experience chronic pain is evident from recent surveys. However, pain has not received enough attention in the overall management of thalassemia. The association of pain with the type and treatment of thalassemia or with its comorbidities is unclear. Abnormal spine imaging is seen in patients reporting pain, although the role of osteopenia has not been established. Pain becomes more frequent with age. The lower back is the most common site and can be particularly disabling and difficult to treat. Treatable causes, such as extramedullary masses or disc herniation or fractures, must be ruled out. Some adults experience increasing pain when the hemoglobin drops at the end of transfusion cycles. Interdisciplinary management of pain is necessary, while overreliance on medications can be counterproductive. The impact of chronic pain on the quality of life must be acknowledged. Physical therapy, psychological counseling, and vocational rehabilitation are vital to management. I recommend a proactive approach for prevention of pain by maintaining optimal bone density and an active lifestyle. I further propose that a universal tool be adopted to document and characterize pain at routine clinic visits.