Interleukin-1, tumour necrosis factor, and growth hormone releasing hormone form part of the humoral mechanisms regulating physiological sleep. Their injection enhances non-rapid-eye-movement sleep whereas their inhibition reduces spontaneous sleep and sleep rebound after sleep deprivation. Changes in their mRNA levels and changes in their protein levels in the brain are consistent within their proposed role in sleep regulation. Furthermore, results from transgenic and mutant animals also are suggestive of their role in sleep regulation. The sites responsible for the growth hormone releasing hormone somnogenic activity seem to reside in the anterior hypothalamus/basal forebrain. Somnogenic sites for interleukin-1 and tumour necrosis factor likely include the anterior hypothalamus, but also may extend beyond that area. These substances elicit non-rapid-eye-movement sleep via a biochemical cascade that includes other known sleep regulatory substances.