The period circadian clock 2 (per2) gene plays an important role in modulating the circadian rhythm in the central nervous system. Its protein product, PER2, is mainly expressed in the suprachiasmatic nucleus (SCN) and limbic system, including the central nucleus of the amygdala (CeA), the bed nucleus of the stria terminalis (BNST) and the hippocampus. PER2 rhythmic expression regulates hypothalamus‑pituitary‑adrenal (HPA) axis excitability and circadian rhythm via integration of optical signals and corticotropin‑releasing factor (CRF) stress‑related neurotransmitters, resulting in circadian rhythmicity in target organs. Moreover, glucocorticoids and glucocorticoid receptors exert strong negative feedback to the HPA axis and certain regions of the limbic system, modulating rhythmic per2 expression in peripheral organs. To date, the mechanism of action of PER2 in the limbic system and the HPA axis remains unclear, yet the per2 gene is considered valuable in clinical research for the study of metabolic syndromes, functional gastrointestinal disorders and certain liver diseases. In this review, we summarize the biological effects of the per2 gene and its protein product, PER2, in the limbic system, its involvement in regulation of the HPA axis by the limbic system and the resulting effects on the biological rhythm of target organs, and its clinical significance.