Adenosine modulates several physiological functions in the CNS and in peripheral tissues via membrane receptors which have been classified into four adenosine subtypes. A1 activation produces neuronal depression: this inhibition allows A1 agonists to produce ischemic tolerance and protection in neuronal tissue. In order to selectively reproduce these effects, several A1 selective ligands have been synthesised and evaluated to understand how they interact with the adenosine A1 receptor. The investigation methods include SAR studies using native and chemically modified A1 receptors, molecular cloning of native and mutant adenosin A1 receptors, molecular modeling and thermodynamic analysis of drug-receptor interaction. Despite the great quantity of information available on the adenosine A1 receptor, no A1 agonist has so far entered in clinical use against brain diseases in view of the side effects, moreover selective A1 agonists appear to be poorly adsorbed into the brain and can be quickly degraded in vivo or in the whole blood. In an attempt to overcome these problems studies have been undertaken dealing with the use of partial agonists to inhibit side-effects and the employment of prodrugs to increase stability and diffusion through lipid barriers of A1 ligands. Other attempts involve either the use of A1 receptor enhancers as modulators able to locally enhance the action of endogenously produced adenosine, or the encapsulation of A1 agonists in drug delivery systems targeted to the brain. In this review, these approaches will be described together with the effects of adenosine A1 receptor ligands and their binding mechanisms on the central nervous system.