Since the early descriptions of sickle cell anemia, it has been clear that genotype at a single locus rarely completely predicts phenotype. This paper reviews explanations for phenotypic variability in some monogenic diseases. In cystic fibrosis, there is strong correlation between genotype and pancreatic phenotype but only weak association with respiratory phenotype, possibly due to differential inheritance of alleles at loci controlling susceptibility to respiratory infection. In addition, disease mutations have been shown to have more or less severe effect, depending on other variation within the cystic fibrosis gene. In phenylketonuria, genotype at the phenylalanine hydroxylase locus appears to explain the biochemical phenotype, but not the intellectual status. There may be genetically determined variation in flux through the minor metabolic pathways for phenylalanine, influencing levels of alternative metabolites involved in mental development. Phenotypic discordance in sickle cell anemia and beta-thalassemia has been associated with the co-inheritance of genes for hereditary persistence of fetal hemoglobin. A mouse locus has been identified that influences tumour number in mice with the multiple intestinal neoplasia gene. Understanding of the genetic interactions that determine phenotype in apparently monogenic diseases should lead to clarification of the role of different genes in polygenic diseases with complex inheritance patterns, as well as enhancing the ability to predict the outcome of a disease mutation.