ObjectiveTo systematically summarize the molecular mechanisms, multimodal localization, and genetic stratification-based management strategies of primary hyperparathyroidism (PHPT), and to offer theoretical references for the precision diagnosis and treatment of PHPT. MethodRelevant literature on the molecular mechanisms, multimodal localization, and genetic stratification-based treatment of PHPT was retrieved from domestic and international databases and systematically reviewed. ResultsThe pathogenesis of PHPT involves cell cycle dysregulation driven by MEN1 and CCND1, impaired negative feedback of calcium homeostasis resulting from mutations in the CaSR (calcium-sensing receptor) and GNA11 (guanine nucleotide-binding protein subunit alpha-11), and the risks of malignant transformation associated with CDC73 mutations. Combined ultrasonography and radionuclide imaging can significantly enhance preoperative localization accuracy. Four-dimensional computed tomography (CT) yields high localization success rates for solitary parathyroid adenomas, whereas 18F-fluorocholine PET-CT exhibits excellent diagnostic performance in patients with negative 99mTc-MIBI (technetium-99m methoxyisobutylisonitrile) findings or multiglandular disease. Germline genetic testing is recommended for patients with early-onset PHPT, recurrent or multiglandular parathyroid disease, or suspected parathyroid carcinoma to guide the extent of surgical resection and avoid unnecessary bilateral neck exploration. Minimally invasive parathyroidectomy is the gold standard for solitary parathyroid adenomas. Ablation therapy is a viable option for patients who are unfit for surgery, whereas pharmacotherapy should be tailored according to whether hypercalcemia or skeletal disease is the predominant feature. ConclusionsPrecision management of PHPT requires the integration of four core pillars: biochemical characterization, molecular mechanisms, multimodal imaging, and genetic stratification. A stratified diagnostic framework coupled with a tiered clinical pathway can overcome the traditional “one-size-fits-all” empirical treatment model and establish a standardized closed-loop system of “screening–referral–follow-up”, thereby improving overall diagnostic yield and therapeutic outcomes.