Sickle cell disease (SCD) and β-thalassemia, two monogenic diseases caused by mutations in the β-globin gene, affect millions of individuals worldwide. These hemoglobin disorders are characterized by extreme clinical heterogeneity, complicating patient management and treatment. A better understanding of this patient-to-patient clinical variability would dramatically improve care and might also guide the development of novel therapies. Studies of the natural history of these β-hemoglobinopathies have identified fetal hemoglobin levels and concomitant α-thalassemia as important modifiers of disease severity. Several small-scale studies have attempted to identify additional genetic modifiers of SCD and β-thalassemia, without much success. Fortunately, improved knowledge of the human genome and the development of new genomic tools, such as genome-wide genotyping arrays and next-generation DNA sequencers, offer new opportunities to use genetics to better understand the causes of the many complications observed in β-hemoglobinopathy patients. Here I discuss the most important factors to consider when planning an experiment to find associations between β-hemoglobinopathy-related complications and DNA sequence variants, with a focus on how to successfully perform a genome-wide association study. I also review the literature and explain why most published findings in the field of SCD modifier genetics are likely to be false-positive reports, with the goal to draw lessons allowing investigators to design better genetic experiments.