Physical activity (PA) is important to human health, and the genetic and biological regulating factors of physical activity are only beginning to be understood. The dopamine (DA) system has been shown to regulate motivation, and locomotor behavior in animals, and this research was designed to understand the dopaminergic factors important in regulating voluntary physical activity in mice. First, the repeatability of measuring exercise endurance vs. wheel running (WR) in different inbred strains of mice was investigated. It was found that WR behavior is a highly repeatable measurement, while exercise capacity measurements showed low repeatability in Balb/cJ mice. Next, expression levels of the five DA receptors, Tyrosine hydroxylase (TH), and the dopamine transporter (DAT) in the nucleus accumbens and striatum were studied in mice with or without wheel access in differentially active inbred strains of mice. No differences in expression levels of any DA receptors were found within strain between group, suggesting level of PA did not affect DA receptor expression. High active C57L/J mice had significantly decreased expression of Drd1 and TH compared to low active C3H/HeJ mice indicating DA receptor, and enzyme expression/function may act independently to control level of PA. Pharmacological studies showed C57L/J mice significantly decrease WR in response to a D1 agonist, and C3H/HeJ mice significantly increase WR in response to a DAT inhibitor. These results suggest genetic differences in the DA system may mediate differences in PA behavior between inbred strains of mice.