Adenosine is a candidate sleep substance. It can be both a distress signal of importance in pathology and a physiological regulator. Key factors in determining which of these possibilities pertain are: (i) the number of receptors expressed, and (ii) the mechanisms that establish extracellular adenosine levels. The roles of adenosine are studied by means of antagonists and/or animals (mostly mice) with targeted deletions of receptors or enzymes involved in adenosine metabolism. Whereas adaptive changes in the genetically modified mice can occur for the physiologically important effects, such adaptive changes are less likely to occur in situations where adenosine acts as a distress signal. The relevance to sleep will be covered only in general terms in this review and will be covered in other contributions to this volume.