The mechanisms by which abused inhalants exert their neurobehavioral effects are only partially understood. In research with other drugs of abuse, specific inbred mouse strains have been useful in exploring genetic loci important to variation in behavioral reactions to these drugs. In the present investigation, mice from three inbred strains (Balb/cByj, C57BL/6J and DBA/2J) and one outbred strain (Swiss Webster) were studied for their acute and chronic sensitivity to toluene-induced changes in locomotor activity. Mice were exposed to toluene (0, 100, 2000, 8000, 10000 ppm) for 30 min in static exposure chambers equipped with activity monitors. In the acute condition, concentrations of toluene <8000 ppm increased ambulatory distance while the concentrations of ≥8000 ppm induced temporally biphasic effects with initial increases in activity followed by hypoactivity. Between-group differences in absolute locomotor activity levels were evident. The inbred Balb/cByj and DBA/2J strains as well as the outbred Swiss Webster strain of mice showed greater increases in activity after an acute challenge exposure to 2000 ppm than the inbred C57BL/6J strain. The same animals were then exposed 30 min/day to 8000 ppm toluene for 14 consecutive days. Re-determination of responses to 2000-ppm challenge exposures revealed that sensitization developed in locomotor activity and that the DBA/2J strain showed the greatest increase in sensitivity. These baseline differences in acute sensitivity and the differential shifts in sensitivity after repeated exposures among the inbred mouse strains suggest a genetic basis for the behavioral effects to toluene. The results support the notion that like for other drugs of abuse, using various strains of mice may be useful for investigating mechanisms that underlie risk for inhalant abuse.