The seemingly unpredictable response to levodopa in patients with Parkinson's disease can be understood as an interaction between several distinct pharmacological effects of levodopa. The most important are a short‐duration response with a half‐life of minutes to hours and a long‐duration response with a half‐life of days, superimposed on diurnal motor variation. A negative response characterized by brief worsening before and after the short‐duration response and dyskinesia accentuate the short‐duration response. These various responses are modified by disease progression and long‐term levodopa therapy. Pharmacodynamic modeling of the short‐duration response indicates that with time, the response becomes less graded and small changes in levodopa concentrations can produce big changes in response. In this setting, unpredictability arises from the variation in absorption and distribution of levodopa.