After identification of the hereditary haemochromatosis gene HFE, and receipt of confirmation that most patients with the condition were homozygous for a single, founder mutation (C282Y), most assumed that C282Y would be a prevalent, highly penetrant mutation in a gene that plays a key part in the regulation of iron absorption and of whole-body iron homoeostasis. With carrier rates of between 10% and 15%, and a homozygote frequency of about one-in-150 in people of northern European descent, C282Y is certainly prevalent. However, it is not highly penetrant. The pronounced variation in phenotype in individuals with the same gene mutation has prompted the search for modifier genes at other loci, and for environmental factors that might affect expression of the condition. Progress in our understanding of how HFE regulates the absorption of dietary iron has been slow, but much can be learnt from the study of the rare instances of haemochromatosis that involve mutations in newly-identified iron-metabolism genes, such as TFR2--a transferrin receptor isoform--and ferroportin1/Ireg1/mtp1--an intestinal iron transporter. The availability of definitive information on penetrance and the identity of genetic modifiers will aid the debate on whether population screening for haemochromatosis should be undertaken or whether alternative strategies should be implemented to improve early detection.