The disorders of hemoglobin, including sickle cell disease (SCD) and β-thalassemia, are the most common “Mendelian” genetic diseases in the world. Numerous studies have demonstrated the complexity in making genotype–phenotype correlations in both SCD and β-thalassemia. Indeed, patients with exactly the same set of pathogenic globin mutations can have dramatically variable clinical courses. We discuss natural history studies that have attempted to delineate the factors responsible for the variability among the numerous clinical complications noted in these diseases. We then discuss, in depth, two well characterized ameliorating factors in the β-hemoglobin disorders, concomitant α-thalassemia, and elevated levels of fetal hemoglobin (HbF). We use the study of HbF regulation to illustrate how important insights into the genetic modifiers in Mendelian diseases can be achieved through the study of such factors. We finally go on to discuss future avenues of research that may allow us to gain further insight into the poorly understood clinical heterogeneity of this fascinating set of common genetic diseases.