Despite clinical experience with levodopa for more than three decades, the role of this agent in the treatment of Parkinson's disease (PD) has not been well defined. Clearly the most effective antiparkinsonian drug, levodopa, is associated with emergence of motor complications, particularly fluctuations and dyskinesias, as well as other side effects. In addition to these limitations, there is an ongoing debate about the potential neurotoxic effects of levodopa, suggested by some in vitro studies. However, there is no support for levodopa-induced neurotoxicity from in vivo studies. This review discusses possible mechanisms of levodopa-related complications and therapeutic strategies for their prevention and management.