The development and characterization of transgenic animal models with genetic manipulation over the last decade has significantly broaded our knowledge of adenosine receptor neurobiology, particularly their involvement in various pathological processes of neuropsychiatric disorders. In this review, we summarize the contributions made to the field of adenosine research by transgenic animal models with either target deletion or over-expression of adenosine receptor subtypes and molecules involved in adenosine metabolism pathways. The available data on the various aspects of physiological (e.g. sleep, motor activity, memory, anxiety, agression and depression and vascular function) and pathological (e.g. ischemia, inflammation, neurodegenerative diseases such as Parkinson’s Disease, Huntington’s Disease, multiple sclerosis, seizures and pain) actions of adenosine as revealed by these transgenic animal models are reviewed. The phenotypes revealed by pharmacological, neurochemical and molecular analyses of these transgenic models into the neuromodulatory function of adenosine receptors in the brain and the homeostatic function of adenosine receptors both in physiological and pathological conditions. These analyses, in many cases, also provided compelling evidence for the phenotypes of adenosine receptor transgenic models that differ from adenosine pharmacological studies, indicating complex actions of adenosine receptors. The complex interplay of adenosine receptors and actions in different cell types and subcellular elements is an important aspect of adenosine’s role that requires new transgenic models designed to target specific brain regions, cell types or subcellular elements. Ultimately these studies should prove important in defining strategies for adenosine-based therapeutical approaches for neuropsychiatric disorders.