Time-dependent sensitization (TDS) is a phenomenon described in rodents as an enhancement in the behavioral and neurochemical responses to intermittent exposure to psychostimulant drugs. Time-dependent sensitization also occurs after repeated encounters with environmental stress. Several features of TDS parallel those of multiple chemical sensitivity (MCS) in humans, and these similarities have led to the hypothesis that MCS may be explained in part by a similar sensitization process that occurs in rodents. In the studies presented here, we discuss some of the critical features of TDS following repeated exposure to cocaine and environmental stress, including the anatomical and neurochemical pathways utilized in expressing TDS. In addition, we discuss the possible neurochemical basis for individual differences in responsiveness to stimuli, including novelty and cocaine. The striking similarities between TDS and MCS suggest it may be possible to develop an animal model of MCS, using TDS in rodents as its basis.