OBJECTIVE Krüppel-like factor 1 (KLF1) regulates most aspects of erythropoiesis. Many years ago, transgenic mouse studies implicated KLF1 in the control of the human γ-globin to β-globin switch. In this review, we will integrate these initial studies with recent developments in human genetics to discuss our present understanding of how KLF1 and its target genes direct the switch. RESULTS Recent studies have shown that human mutations in KLF1 are common and mostly asymptomatic, but lead to significant increases in levels of fetal hemoglobin (HbF) (α2γ2) and adult HbA2 (α2δ2). Genome-wide association studies (GWAS) have demonstrated that three primary loci are associated with increased HbF levels in the population: the β-globin locus itself, the BCL11A locus, and a site between MYB and HBS1L. We discuss evidence that KLF1 directly regulates BCL11A, MYB and other genes, which are involved directly or indirectly in γ-globin silencing, thus providing a link between GWAS and KLF1 in hemoglobin switching. CONCLUSIONS KLF1 regulates the γ-globin to β-globin genetic switch by many mechanisms. Firstly, it facilitates formation of an active chromatin hub (ACH) at the β-globin gene cluster. Specifically, KLF1 conscripts the adult-stage β-globin gene to replace the γ-globin gene within the ACH in a stage-specific manner. Secondly, KLF1 acts as a direct activator of genes that encode repressors of γ-globin gene expression. Finally, KLF1 is a regulator of many components of the cell cycle machinery. We suggest that dysregulation of these genes leads to cell cycle perturbation and 'erythropoietic stress' leading to indirect upregulation of HbF.