Adenosine is a well known neuromodulator in the central nervous system. As a consequence, adenosine can be beneficial in certain disorders and adenosine receptors will be potential targets for therapy in a variety of diseases. Adenosine receptors are G protein-coupled receptors, and are also expressed in a large variety of cells and tissues. Using these receptors as a paradigm of G protein-coupled receptors, the present review focus on how protein-protein interactions might contribute to neurotransmitter/neuromodulator regulation, based on the fact that accessory proteins impinge on the receptor/G protein interaction and therefore modulate receptor functioning. Besides affecting receptor signaling, these accessory components also play a key role in receptor trafficking, internalization and desensitization, as it will be reviewed here. In conclusion, the finding of an increasing number of adenosine receptors interacting proteins, and specially the molecular and functional integration of these accessory proteins into receptorsomes, will open new perspectives in the understanding of particular disorders where these receptors have been proved to be involved.