A meta-analytical review of 20 studies (n = 3907) of the association between DRD4 polymorphism and novelty seeking suggests the following conclusions: (a) on average, there is no association between DRD4 polymorphism and novelty seeking (average d = 0.06 with 95% CI of +/- 0.09), where 13 reports suggest that the presence of longer alleles is associated with higher novelty seeking scores and seven reports suggest the opposite; (b) there is a true heterogeneity among the studies (ie, unknown moderators do exist) but the strength of the association between DRD4 polymorphism and novelty seeking in the presence of any (unknown) moderator is likely to be weak; (c) search for moderators has not yielded any reliable explanation for the variability among studies. We propose that to find such moderators, theory-driven research for potential interaction, coupled with larger sample sizes should be employed. The growing availability of powerful statistical techniques, high-throughput genotyping and large numbers of polymorphic markers such as single nucleotide polymorphisms makes such proposed studies increasingly feasible.