Huntington’s (HD) and Parkinson’s diseases (PD) are neurodegenerative disorders caused by the death of GABAergic and dopaminergic neurons in the basal ganglia leading to hyperkinetic and hypokinetic symptoms, respectively. We review here the participation of purinergic receptors through intracellular Ca²⁺ signaling in these neurodegenerative diseases. The adenosine A_2A receptor stimulates striatopallidal GABAergic neurons, resulting in inhibitory actions on GABAergic neurons of the globus pallidus. A_2A and dopamine D2 receptors form functional heteromeric complexes inducing allosteric inhibition, and A_2A receptor activation results in motor inhibition. Furthermore, the A_2A receptor physically and functionally interacts with glutamate receptors, mainly with the mGlu5 receptor subtype. This interaction facilitates glutamate release, resulting in NMDA glutamate receptor activation and an increase of Ca²⁺ influx. P2X7 receptor activation also promotes glutamate release and neuronal damage. Thus, modulation of purinergic receptor activity, such as A_2A and P2X7 receptors, and subsequent aberrant Ca²⁺ signaling, might present interesting therapeutic potential for HD and PD.