The hypocretins (also known as orexins) and their receptors are the focus of many investigators as sites for therapeutic intervention in a number of endocrinologic, neurologic and sleep disorders. The interest for the hypocretin system is highlighted by a recent discovery that a human sleep disorder, narcolepsy, is tightly linked with the deficiency of hypocretin peptides. This finding suggests that hypocretin replacement is a promising new therapeutic intervention for human narcolepsy and related disorders, but this will only become possible when small-molecule (i.e., non-peptide) hypocretin receptor agonists become available. In contrast, high-throughput screening efforts in hypocretin receptor drug discovery programs by a number of pharmaceutical companies have already identified novel small-molecule hypocretin receptor antagonists and these antagonists may be used for the treatment of insomnia, especially for sleep-initiation problems. This is because hypocretin-deficient narcoleptic subjects show very short sleep latency and the blockade of the hypocretin receptor may induce a similar sleep symptom. At least two hypocretin receptor antagonists (ACT-078573 and GW-649868) are presently under development for the treatment of human insomnia and the promising aspects and limitations of these therapeutic interventions are discussed in this paper.