Dopamine replacement therapy effectively treats the early motor symptoms of Parkinson's disease (PD). However, its association with the development of motor complications limits its usefulness in late stages of the disease. Adenosine A(2A) receptors are localised to the indirect striatal output function and control motor behaviour. They are active in predictive experimental models of PD and appear to be promising as the first major non-dopaminergic therapy for PD. Istradefylline is a novel adenosine A(2A) receptor antagonist currently in Phase III clinical trials for efficacy in patients with PD; results from Phase II clinical trials demonstrated that it provides a clinically meaningful reduction in 'off' time and an increased 'on' time with non-troublesome dyskinesia in levodopa-treated patients with established motor complications, and is safe and well tolerated.