Parkinson's disease (PD) is a multisystemic disorder in which several neurotransmitters other than dopamine are affected. Drugs acting on non-dopaminergic systems are envisaged as promising agents to treat PD and levodopa-induced dyskinesias (LID). However, compounds targeting glutamate, adenosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed in human studies showing negative, inconsistent or unsatisfactory results. Most of these drugs had been tested previously in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, as well as in the classic 6-hydroxydopamine-lesioned rat model. These failures raise several questions and concerns about the true reliability of animal studies, the adequacy of the working hypotheses and design of clinical trials, the validity of tools in current use to evaluate a particular effect, and the selectivity of the drugs used. More importantly, observed discrepancies between the results in models and patients, could challenge the validity of current ideas about the pathophysiology of parkinsonism and LID.