Thalassemia is a group of hereditary hemoglobinopathies. It is one of the most common genetic disorders worldwide, presenting major public health and social challenges in high incidence areas. Thalassemia is inherited in an autosomal recessive manner. It is manifested as chronic hemolytic anemia, which is caused by partial or complete lack of the synthesis of alpha- or beta-globulin chains that form hemoglobin. Thalassemia major (TM) is associated with the most serious clinical changes and life-threatening risk and is characterized by the triad of chronic anemia, ineffective erythropoiesis, and iron overload. Anemia can be treated with regular blood transfusions, but this life-saving therapy results in a “second disease” due to iron accumulation in the body tissues. Iron overload is the main cause of morbidity and mortality. The oral and maxillofacial features of TM are protruding frontal and malar bones, thinning of the mandibular inferior cortex, small maxillary sinuses, maxillary hypertrophy, and flaring of the maxillary anterior teeth. Dental complications of TM include dental caries, periodontal disease, reduction in tooth size, teeth spacing, short and narrow dental arches, delayed tooth development, malocclusion. This monograph discusses the epidemiology, pathophysiology, clinical manifestations, radiological characteristics, dental care, management and complications. Guidelines for dental care are presented and stratiges of thalassemia prevention are reviewed.