HbH disease had been introduced as a mild anemia disease. It recently has become the most challenging hemoglobinopathy due to the increasingly described genotype patterns and very variable phenotypic presentations in different ethnics. Phenotypic severity of HbH syndrome is not simply related to the degree of α-globin deficiency and being influenced by several environmental and/or genetic factors. Hence, more investigation needs to identify factors like other genetic loci linked and/or unlinked to the α-globin genes affecting molecular mechanisms that influence clinical expression of HbH disease. Altogether, the complicated pathophysiology of HbH disease makes it to be known as a poorly understood syndrome. It may offer the hypothesis that it is a multifactorial disease, which needs to be investigated by more comprehensive genetic approach like genome wide association studies (GWAS) looking for genetic variants. Moreover, extended haplotype analysis to find out probable specific association between haplotypes of modifier genes and disease severity in patients with a specific HbH genotype may be a key point. In this review, we aim to provide important information regarding phenotypic presentation of different genotypes that have been described worldwide. It may help geneticists regarding challenging health care aspects of HbH disease in a specific ethnic.