β-thalassemia (β-thal) is a fatal and disabling inherited blood disorder with diverse phenotypes. The same or similar genotype of β-thal can manifest variable clinical severities. It is the hotspot and emphasis in the field of hematopathy and genetic diseases to explore genetic modifiers that influence the phenotype of β-thal. This review illustrates the deteriorating and amelioratig modifiers from two aspects: genotypes of α-globin and quantitative trait locus of fetal hemoglobin (Hb F). Variations of transcription factors which reactive the γ-globin gene expression and β-globin cluster cis-acting elements were introduced emphatically. Finally, clinical applications and future development prospects of β-thal genetic modifiers are introduced by examples.