Thalassemia is a quantitative problem of too few globins synthesized, whereas sickle-cell disease (a hemoglobinopathy) is a qualitative problem of synthesis of an incorrectly functioning globin. Thalassemias usually result in underproduction of normal globin proteins, often through mutations in regulatory genes. Hemoglobinopathies imply structural abnormalities in the globin proteins themselves. The two conditions may overlap, however, since some conditions that cause abnormalities in globin proteins (hemoglobinopathy) also affect their production (thalassemia). Thus, some thalassemias are hemoglobinopathies, but most are not. Either or both of these conditions may cause anemia.

The two major forms of the disease, alpha- and beta- (see below), are prevalent in discrete geographical clusters around the world - it is presumed associated with malarial endemicity in ancient times. Alpha is prevalent in peoples of Western African and South Asian descent. It is nowadays found in populations living in Africa and in the Americas. It is also found in Tharu in the Terai region of Nepal and India. It is believed to account for much lower malaria morbidity and mortality, accounting for the historic ability of Tharus to survive in heavily malarial areas where others could not.

Beta thalassemia is particularly prevalent among Mediterranean peoples, and this geographical association is responsible for its naming: Thalassa (θάλασσα) is Greek for the sea, Haema (αἷμα) is Greek for blood. In Europe, the highest concentrations of the disease are found in Greece, coastal regions in Turkey, in particular, Aegean Region such as Izmir, Balikesir, Aydin, Mugla, and Mediterranean Region such as Antalya, Adana, Mersin, in parts of Italy, in particular, Southern Italy and the lower Po valley. The major Mediterranean islands (except the Balearics) such as Sicily, Sardinia, Malta, Corsica, Cyprus, and Crete are heavily affected in particular. Other Mediterranean people, as well as those in the vicinity of the Mediterranean, also have high rates of thalassemia, including people from West Asia and North Africa. Far from the Mediterranean, South Asians are also affected, with the world's highest concentration of carriers (16% of the population) being in the Maldives.