In this review we shall attempt to summarize the literature published on the high responders/low responders' animal model of drug addiction. This model is based on the locomotor activity of rats in the mild stress of a novel environment. Rats that exhibit high rates of exploratory behaviours are deemed high responders (HR) and rats that exhibit low exploratory behaviours are deemed low responders (LR). Interestingly, the rate of these exploratory behaviours predicts the response of these animals to drugs of abuse. In this manuscript we will review the behavioural and physiological differences between HR and LR rats in response to d-amphemtamine, cocaine, morphine, alcohol and nicotine.