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The catechol-O-methyltransferase (COMT) gene has attracted strong neuroscientific interest due to its implication in dopaminergic neurotransmission. One of its most widely studied variations comprises a common single nucleotide polymorphism (SNP), a valine-to-methionine substitution at codon 158 (COMT Val158Met), which has been associated with various cognitive phenotypes, psychiatric disorders and changes in brain activation and structure. This review first gives an overview of recent findings on the effect of COMT Val158Met carrier status on behavioral and imaging correlates of brain function. Here, we highlight not only commonalities but also disparate findings and open questions, and identify possible causal factors including gender effects, study population characteristics, and definition of the respective phenotypes. Next, an introduction to what is known about interactions of COMT allele carrier status …