Rare diseases are rare: by definition, a rare disease affects less than 5 in 10,000 people. However, rare diseases are in fact common, as between 6,000 and 8,000 different rare diseases are known; this adds up to more than 4 million people with a rare disease in the UK. Rare diseases are neglected, they are often misdiagnosed or diagnosed with a major delay, and only 250 rare diseases have a specific code in the International Classification of Diseases of the WHO so far. The lecture will highlight how recent advances in genetics and genomics have elucidated the pathobiology of rare single-gene skin disorders using the example of congenital ichthyoses. Our understanding of the role played by the sphingolipid metabolism in the epidermis has now opened new avenues for the development of drugs that are effective for causal therapies of these disabling disorders.