This review aims to profile the disease of thalassemia in Malaysia and to identify the challenges that have kept Malaysia from effectively reducing the birth rate of thalassemia patients. The success of thalassemia prevention programs in some countries have shown that more than 90% of the reduction of cases were achieved by using retrospective screening method (prenatal, premarital, retrospective counselling). However, in Malaysia any impact of the prevention program is yet to be visible, and a reduction in new births of thalassemia patients remains to be seen. The number of patients in the national thalassemia registry (www.mytalasemia.net.my) is increasing over the years from 3588 in 2008 to 4990 in 2010 and to 6624 in 2015. The provision of quality care and disease management imposes a huge economic burden on national health resources, which is why an effective prevention program is urgently needed. For Malaysia to reduce the burden of new thalassemia cases, it is vital to address gaps and limitations of the existing preventive strategies. The screening program has to be integrated into existing primary healthcare settings, promoted to every party including the higher ministry bodies and designed to adapt to the highly diverse local religious and cultural backgrounds. Through continuous support by the government, health care providers and the general public, there is hope that prevention and control of this disease may be achieved in the future.