Metastatic carcinomas of unknown primary origin (cancer of unknown primary-CUP) represent 3-5% of all cancers. This term includes all patients presented with metastatic disease in whom the primary site could not have been identified. Despite the use of modern and comprehensive diagnostic techniques and procedures, there is no improvement in efficacy (efficiency) of indentifying the primary site of disseminated disease. That is why a diagnostic procedure should be rational and should include the basic diagnostic examination (analyses) with the aim to define biological and clinical characteristics of diagnosed disease, as well as an optimal therapeutic approach. Although the overall prognosis of the majority of these patients is poor, it is possible, nowadays, to distinguish the subgroups of patients with favorable prognosis. Results of new basic research, better understanding of pathogenesis at the molecular level and introduction of new drugs through clinical trials suggest an advance in this disease treatment and outcome.