There is evidence that the dopaminergic system is involved in probabilistic reinforcement learning and reward‐related decision‐making. However, little is known about the effects of external dopaminergic challenges on processing of uncertainty in decision‐making tasks. Therefore, the present study examined changes in fMRI activation patterns in a natural sampling paradigm. Decision making under uncertainty was examined before and after administration of a single dose of 40 mg methylphenidate as an acute dopaminergic pharmacological challenge. We found that the level of uncertainty was positively correlated with activations in the prefrontal cortex. Conversely, negative correlations with uncertainty were found in the left hippocampus, right amygdale, and right middle temporal gyrus. The drug intervention with methylphenidate revealed a differential picture. Uncertain information processing was associated with higher activation in the parietal association cortex and posterior cingulate cortex after placebo relative to methylphenidate. The methylphenidate challenge relative to placebo was associated with higher left and right parahippocampal as well as cerebellar activation under uncertainty. Apparently, the pro‐dopaminergic pharmacological influence induces a relative shift towards recruitment of hippocampal areas under uncertainty, whereas under placebo conditions, higher levels of parietal cortex activations are involved in the task. The findings suggest a role of dopamine in uncertainty processing and shed light on the pharmacological mechanisms of methylphenidate. Synapse 63:429–442, 2009. © 2009 Wiley‐Liss, Inc.