Cancer of unknown primary site (CUP) is not a rare tumour. It accounts as the seventh to eighth most frequently diagnosed cancer in a general medical oncology service. Since CUP is not a homogeneous disease and it consists of different favourable and unfavourable sub-sets, treatment of each clinicopathological entity requires a unique approach. The spectrum of therapeutic management includes both locoregional and systemic therapy and should intend to offer optimal benefit to favourable CUP patients and palliative care to unfavourable cases. This review article provides both a historical outline of CUP treatment as well as a helpful therapeutic guide to every oncologist who treats CUP patients.