Laboratory rodents are generally maintained under standardized conditions in order to control the effects of extrinsic factors on research. However, despite attempts to standardize conditions, variability can nonetheless confound efforts directed toward research reproducibility. Here we explore some of the existing literature on the potential impact of seasonal variability as an extrinsic factor that can potentially impact research results. We discuss the influence of seasonal changes in association with an internal clock mechanism that might account for such variation, noting that the mechanisms and interactions of seasonal and internal time-keeping remain largely undetermined. Finally, we speculate that seasonal changes experienced by personnel who handle animals may influence the animals in ways that result in physiologic and behavioral changes.