Congenital anemias are a wide spectrum of diseases including hypoproliferative anemia syndromes, dyserythropoietic anemias, sideroblastic anemias, red blood cell membrane and enzymatic defects, hemoglobinopathies, and thalassemia syndromes. The various congenital anemia syndromes may have similar clinical and laboratory presentations, making the diagnosis challenging. The traditional work-up, which includes a complete blood count, blood smears, bone marrow studies, flow cytometry, and the osmotic fragility test, does not always lead to the diagnosis. Specialized tests such as red blood cell enzyme activity and ektacytometry are not widely available. In addition, red blood cell transfusions may mask some of the laboratory characteristics. Therefore, genetic testing is crucial for accurate diagnosis of patients with congenital anemias. However, gene-by-gene testing is labor intensive because of the large number of genes involved. Thus, targeted next-generation sequencing using custom-made gene panels has been increasingly utilized, with a high success rate of diagnosis. Accurate genetic diagnosis is important for determining specific therapeutic modalities, as well as for avoiding splenectomy when contraindicated. In addition, molecular diagnosis can allow for genetic counseling and prenatal diagnosis in severe cases. We suggest a work-up scheme for patients with congenital anemias, including early incorporation of targeted next-generation sequencing panels.