Major motor fluctuations in patients with Parkinson's disease during levodopa treatment include "wearing-off" fluctuations, "on-off" fluctuations, freezing, and early morning dystonia. Other fluctuations, such as drug resistant "off periods," complicated "end-of-dose" effects and "resistant fluctuators" can also occur. In this paper, the underlying pathophysiologic mechanisms of the major motor fluctuations are reviewed, and practical approaches to manage these problems are discussed. "Wearing-off" fluctuations are most common, and several different mechanisms appear to be operating, including the interference of food in the gastrointestinal absorption of levodopa, inhibition of transport of levodopa to the brain by large neutral amino acids or 3-O-methyldopa, and progression of the degeneration of dopaminergic nerve terminals. The mechanisms of "on-off" fluctuations and freezing are not well understood. Loss of cerebral noradrenaline that results from locus coeruleus degeneration may, in part, be responsible for freezing. To minimize the occurrence of these motor fluctuations, multiple classes of antiparkinsonian drugs need to be used, so that the dose of levodopa can be maintained at a reasonably low level.