The initial benefits of levodopa decline for as many as half of all patients with Parkinson's disease treated for 2 years or more. Although levodopa is the most effective means for symptom relief, many parkinsonian patients lose the consistency of optimal symptom control. The variability experienced by such patients may arise from several alternative mechanisms at the level of the central nervous system (e.g., a narrowed therapeutic window for receptor-mediated effects or the loss of storage capability for dopamine in the parkinsonian brain). Whatever the cause, several practical methods have been developed. Dopaminergic agonists have played a major role in improving such problem. There are also several strategies for enhancing levodopa's dose by dose effectiveness, including sustained-release levodopa preparations and enteral infusions of levodopa. Another approach is the use of selegiline (deprenyl), MAO-B inhibitor slowing the breakdown of dopamine and thereby extending the duration of levodopa effect. Although selegiline can lessen the abruptness of levodopa wearing off, it can also exacerbate undesired peak effects of the drug. Clinical trials are planned with levodopa pro-drugs and inhibitors of catechol-O-methyltransferase to learn if these approaches can improve problems of long-term levodopa therapy.