Cancer of unknown primary (CUP) is the 6th most common cause of cancer-related death in Australia. CUP has a dismal prognosis with one and 5-year survival rates of 25% and 14%, respectively. Since cancer medicine is largely based on anatomical location, CUP significantly challenges the established care paradigms. CUP patients are disadvantaged in the access of molecularly targeted therapies through clinical trials or the pharmaceutical benefit scheme (PBS) as known tissue of origin is often a requirement. A strong rationale therefore exists to develop better diagnostic methods for CUP to help resolve the primary origin of a patient’s tumour. In addition, employing precision medicine by identifying mutations that guide targeted treatment offers an alternative to conventional site-directed chemotherapies. Through the “Solving Unknown Primary cancER” (SUPER) study, we have shown that panel-based testing can help resolve a diagnosis in many CUP patients as well as aid in directing targeted treatments based on molecular profiling of the tumour. SUPER-NEXT now seeks to test clinical whole genome and transcriptome (WGTS) sequencing to measure the increased sensitivity over panel-based approaches. Furthermore, the use of “liquid biopsies” to harvest circulating tumour DNA in patient blood, will be tested alongside, and could potentially enable non-invasive and more rapid genomic testing. SUPER-NEXT is a collaborative study involving the Peter MacCallum Cancer Centre, the University of Melbourne, Swinburne University and QIMR-Berghofer recruiting patients from 16 participating clinical sites across six Australian states and territories. The potential benefits of the different tests will be measured through surveying pathologists and medical oncologists before and after the return of genomic test results. Patient reported outcomes are captured at baseline and at 3-months post testing and clinical follow-up at 6, 12 and 18 months. Health system costs and patient health benefits (via changes in patient management) will also be assessed.