This article reviews the molecular bases of alpha- and beta-thalassemias in Sardinia. In addition, it describes the characteristics and the effects of a genetic program designed to prevent homozygous beta-thalassemia. In the large majority of the cases (95.7%), beta-thalassemia is caused by the nonsense mutation at codon 39, followed by frameshifts at codon 6 (2.1%). Homozygous beta-thalassemia most commonly results in thalassemia major, but in a small proportion this genotype produces milder forms referred to as thalassemia intermedia. The reasons for the attenuated forms were determined only in a small proportion of the cases. The reduced clinical severity was due to either of two factors: (a) There could be the presence of cytosine-thymidine (C----T) substitution of position - 158 G gamma, which is able to increase the G gamma chain output (as in homozygotes for frameshift at codon 6 or compound heterozygote for frameshift at codon 6 and codon 39 nonsense mutation). (b) Reduced clinical severity could be the result of co-inheritance of alpha-thalassemia in the form of two alpha-globin gene deletions of functional loss of the alpha 2-globin gene (homozygote for codon 39 nonsense mutation). The most prominent clinical form of alpha-thalassemia is hemoglobin H disease, which may result from the compound heterozygous state for deletion alpha 0- and alpha(+)-thalassemia (in 83.1% of cases) or deletion and nondeletion alpha-thalassemia (in 16.9%). Deletion Hb disease shows a milder clinical picture as compared to the nondeletion form. The most common nondeletion alpha-thalassemia is the ATG----ACG substitution at the initiation codon of the alpha 2 gene. Double heterozygotes of alpha (-alpha/-alpha) and beta-thalassemia or delta- and beta-thalassemia are relatively common and may cause confusion in carrier identification. The preventive program aimed to control beta-thalassemia is based on voluntary carrier screening., counselling, and prenatal diagnosis. Prenatal diagnosis is carried out by dot blot analysis with allelic specific oligonucleotides on amplified trophoblast DNA. This procedure gave very reliable results; in fact, no misdiagnosis has occurred so far. The preventive program was highly effective, resulting in a decline of the incidence of thalassemia major from 1:250 to 1:1,000 live births.