Adenosine A1 and A2A receptors are highly expressed in the basal ganglia (BG), where they functionally modulate the nuclei forming this network. The extensive interactions with dopaminergic and nondopaminergic receptors place the adenosine receptor in a privileged position for controlling voluntary movement in physiological and pathological conditions such as Parkinson's disease (PD) and Huntington's disease (HD). In this chapter, we give an overview of adenosine receptor localization within the BG, with a focus on the A2A receptor and its multiple interactions. Presynaptic and postsynaptic modulations of neurotransmission, together with the role of adenosine at the BG network level, are discussed in relation to PD and HD. We also report the current knowledge on the neuroprotective properties displayed by A2A antagonists in BG pathologies and recent evidence of a role of adenosine in cognitive functions. Finally, results from clinical trials in PD patients with istradefylline, preladenant, tozadenant, and caffeine are reported, which suggest that A2A antagonists may counteract motor impairment without worsening L-3,4-dihydroxyphenylalanine-induced dyskinesia.