Carcinoma of unknown primary remains relatively common and consists of a heterogenous group of cancers that are poorly characterised. There are many limitations of current diagnostic and management algorithms but recent guidelines, both from ESMO and UK-NICE, try to improve and coordinate diagnostic pathways at a country wide level (NICE. 2010. Diagnosis and Management of Metastatic malignant disease of unknown primary origin. NICE. July 2010 http://www.nice.org.uk/CG104). Recent advances in molecular diagnostics technology, and understanding of the basic biology of cancer, have enabled the potential application of molecular profiling to guide clinical management. Modern IHC or molecular profiling technologies can potentially aid in clinical decision making, although there are no randomised studies suggesting that they necessarily add value, either to clinical out-comes or health-economics. This is one of the main questions being tested prospectively in the UK clinical trial called CUP-ONE, which is directly comparing 2 novel diagnostic technologies with a IHC algorithm (Eudract Ref: 2008-000657-35) and is due to complete in 2013. It is possible that these two important diagnostic methods may be complementary in many ways: Molecular profiling assays and/or IHC may be able to identify CUP subsets that respond favorably to active chemotherapy regimens, as used against the corresponding anatomically defined cancers. CUP-ONE is the largest prospective trial looking at the clinico-translational characteristics and outcomes of CUP patients. Clinical and cost- effectiveness studies evaluating the impact of these new diagnostic tools on therapy decisions and survival are ongoing. It appears we are now entering a new era of better understanding of the biological enigma of CUP, and further research will lead toward superior patient outcomes.