Gene targeting allows one to create null mutations in mice and to analyze how the mutant organism responds to the lack of a single gene product. This has facilitated the molecular dissection of such complex characteristics as mammalian brain function and behavior, including learning, memory, aggression, and maternal behavior to mention a few. However, the interpretation of the phenotypical changes that arise in null mutant mice has been questioned. The possibility that genes other than the targeted one may contribute to phenotypical alterations has been raised and the importance of compensatory mechanisms has been brought to attention. This review focuses on recent advances in the literature that illustrate the caveats associated with gene targeting and also presents an overview of potential solutions for the discussed problems.