Although the role of genetics in personality has been studied extensively at a phenomenological level, only lately has the investigation of specific genes been performed. Recent reports suggest that DNA variants of the dopamine D4 receptor gene (DRD4) are associated with the personality trait of novelty seeking; however, others fail to replicate this finding. Such conflicting results suggest either a weak effect, an association only in certain populations, or a false-positive resulting from population stratification. We provide a critical analysis of genetic studies of DRD4 variants with novelty seeking, alcoholism, drug abuse, and attention deficit hyperactivity disorder. Evidence for the role of DRD4 in novelty seeking is inconclusive, with a number of methodological concerns. Use of more conservative statistical criteria for significance, employing gene haplotypes, as well as linkage disequilibrium studies, are recommended. The molecular biology of the D4 gene is also reviewed.