Cancer of unknown primary site (CUP) is a group of diseases where the primary tumor cannot be detected in 2% of patients with metastatic cancer. In postmortem examinations, primary tumors can be found in 75% of these patients, with most tumors being under 10 mm in size. Diagnosis of CUP involves a thorough history and physical examination, blood tests, imaging techniques such as CT scans, and specific investigations for women (breast ultrasound and mammography) and men (prostate-specific antigen). Pathological examinations, including immunohistochemical staining, are also performed. If imaging techniques are insufficient, Positron Emission Tomography (PET) can be conducted. Recent advancements in imaging techniques and molecular profiling have allowed for a novel classification of CUP and individualized treatment approaches. Imaging plays a crucial role in the evaluation of CUP patients, with IV contrast CT scans recommended for all patients. Additional imaging techniques, such as breast MRI for women with isolated axillary lymphadenopathy and testis or gynecological ultrasound for specific cases, may also be used. PET/CT investigation is recommended for cases where lymphadenopathy pathology results suggest squamous cell cancer and the primary site cannot be found. Although there are no prospective studies on this issue, retrospective studies have shown the benefits of PET/CT in these cases.(AI)