Abstract: Microglia cells are the resident innate immune cells of the central nervous system (CNS) (Paolicelli et al., 2022). They play a pivotal role in CNS development and in maintaining homeostasis during adulthood. Microglia are being extensively studied for their involvement in CNS disorders, ranging from autoimmune diseases such as multiple sclerosis to neurodegenerative and psychiatric conditions, as well as stroke and brain tumors (Paolicelli et al., 2022). To harness microglia in therapeutic development, we need to deepen our understanding of their intricate biology. Our knowledge of microglia biology has evolved significantly with technological advancements, leading to a progressive “rethinking” of microglia cells within the field. Initially viewed as static cells, we now understand microglia to be highly motile and constantly surveillant. Once thought to be a homogeneous population of CNS macrophages, microglia are now recognized to occupy a range of cellular states (Paolicelli et al., 2022). Importantly, emerging evidence highlights circadian and diurnal rhythms as key contributors to microglial immune reactivity, morphology, and functions such as phagocytosis (Gu et al., 2023; GuzmánRuiz et al., 2023; Jiao et al., 2024). Circadian rhythms refer to physiological oscillations dictated by the endogenous biological clock, while diurnal rhythms refer to physiological variations set by external light cues that function as Zeitgeber time (ZT, German word for time-giver), such as the lightdark cycle (Guzmán-Ruiz et al., 2023). Currently, most microglial studies do not account for these oscillations, which can significantly impact study design and data interpretation. This perspective article aims to discuss why implementing a circadian framework in preclinical research is essential for advancing our understanding of microglia cells in both physiology and disease.