The remarkable phenotypic diversity of the β-thalassaemias reflects the heterogeneity of mutations at the β-globin locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors. It is likely that phenotype–genotype relationships will be equally complex in the case of many monogenic diseases. These findings highlight the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved. They also emphasize the value of an understanding of phenotype–genotype relationships in designing approaches to gene therapy.