Methylphenidate (Ritalin), a psychostimulant used in the treatment of Attention-Deficit Hyperactivity Disorder, has pharmacological effects similar to cocaine and amphetamine. Clinical use of methylphenidate, as well as diversion and abuse, have significantly increased during the past 10-15 years, heightening concerns regarding the long-term effects of methylphenidate on the developing brain. Here we review the effects of acute and repeated methylphenidate treatment on molecules of neuronal signaling and neuroplasticity (including transcription factors, neuropeptides, and components of second messenger cascades) and compare these molecular effects with those produced by cocaine and amphetamine. Some molecular changes, such as altered transcription factor gene regulation, are similar to those of cocaine and amphetamine. Other effects, notably those on the expression of opioid peptides and postsynaptic density molecules (Homer 1a), differ between methylphenidate and cocaine or amphetamine treatment. These differences support the notion that methylphenidate produces less neuroadaptations than cocaine and amphetamine, and might provide a molecular basis for reduced addiction liability of methylphenidate compared with these other psychostimulants.