The Morris water maze (MWM) has been widely used as a diagnostic tool to detect alterations in hippocampal-dependent learning induced by pharmacological or genetic manipulations in rats and mice. However, with the frequent use of the paradigm some questions have arisen regarding the complex nature of the effects of environmental and biological factors that influence behavioral performance of rodents in this task. One of the most contentious issues is whether MWM can consistently detect genetic differences independent of environmental, i.e., laboratory and experimental conditions. In the present paper, we demonstrate that changes in environmental factors, due to holding mice in large vs. small home cages, can lead to significant and robust spatial learning alterations in one inbred strain (C57BL/6) while having minimal or no effects on another (129/SVEV). The detected genotype-environment interaction underscores the need for experimenters to diligently control and document all possible environmental factors in order to make their results comparable across multiple test environments and laboratories.