Cancer of unknown primary site is a histologically confirmed cancer that manifests in advanced stage, with no identifiable primary site following standard diagnostic procedures. Patients are initially categorized based on the findings of the initial biopsy: adenocarcinoma, squamous-cell carcinoma, neuroendocrine carcinoma, and poorly differentiated carcinoma. Appropriate patient management requires understanding several clinical and pathological features that aid in identifying several subsets of patients with more responsive tumors.