Defective utilisation of background stimuli may result in a large range of cognitive impairments. We describe here three experimental paradigms taxing the processing of contextual information, (i) radial maze learning under distinct cueing conditions and successive context shifts; (ii) reactivity to spatial and object change; (iii) contextual versus cue fear conditioning with pre-test exposure to the experimental context. These paradigms have then been used to characterise the behaviour of null mutant and transgenic mice. In a first series of experiments, we assessed the effect of the null mutation of the gene encoding for Tissue Plasminogen Activator (tPA). Initial investigations pointed to a reduction of the late phase of long-term potentiation in tPA-knock out relative to wild type mice without any consistent performance impairment in several hippocampal-dependent tasks. When tested following our protocols, we found tPA knock out impaired in habituation of object exploration, reactivity to spatial change and contextual fear conditioning. The second example concerns mice overexpressing the mutant human Cu,Zn superoxide dismutase (SOD1) gene, that provide a murine model of amyotrophic lateral sclerosis. We found these mice exhibiting a paradoxical selective enhancement of reactivity to spatial change in comparison with mice overexpressing either the endogeneous murine Cu,Zn SOD1 or the wild type human Cu,Zn SOD1 genes. Our conclusion emphasises the view that experimental protocols involving contextual manipulations may be suitable for differentiating behavioural phenotypes.