The adenosine A_2A receptor has emerged as an attractive non-dopaminergic target in the pursuit of improved therapy for Parkinson's disease (PD), based in part on its unique CNS distribution. It is highly enriched in striatopallidal neurons and can form functional heteromeric complexes with other G-protein-coupled receptors, including dopamine D₂, metabotropic glutamate mGlu₅ and adenosine A₁ receptors. Blockade of the adenosine A_2A receptor in striatopallidal neurons reduces postsynaptic effects of dopamine depletion, and in turn lessens the motor deficits of PD. A_2A antagonists might partially improve not only the symptoms of PD but also its course, by slowing the underlying neurodegeneration and reducing the maladaptive neuroplasticity that complicates standard ‘dopamine replacement’ treatments. Thus, we review here a prime example of translational neuroscience, through which antagonism of A_2A receptors has now entered the arena of clinical trials with realistic prospects for advancing PD therapeutics.