Within the D2-class of dopamine receptors, the D2 and D3 subtypes share the highest degree of similarity in their primary structure. However, the extent to which these two receptor subtypes have similar or different functional properties is unclear. The present study used gene targeting to generate mice deficient for D2, D3, and D2/D3 receptors. A comparative analysis of D2 and D3 single mutants and D2/D3 double mutants revealed that D2/D3 double mutants develop motor phenotypes that, although qualitatively similar to those seen in D2 single mutants, are significantly more severe. Furthermore, increased levels of the dopamine metabolites dihydroxyphenyl acetic acid and homovanillic acid are found in the dorsal striatum of D2 single mutants. The levels of these metabolites, however, are significantly higher in mice lacking D2 and D3 receptors. In addition, results of immunoprecipitation experiments revealed that D2 single mutants express higher levels of D3 receptor proteins during later stages of their postnatal development. These results suggest that D3 receptors compensate for some of the lacking D2 receptor functions and that these functional properties of D3 receptors, detected in mice with a D2 mutant genetic background, remain masked when the abundant D2 receptor is expressed.