Cancer of unknown primary (CUP) is a rare malignancy that presents with metastatic disease and no identifiable site of origin. Most patients have unfavorable features and attempts to treat based on tissue-of-origin identification have not yielded a survival advantage compared with empiric chemotherapy. Next-generation sequencing has revealed genomic alterations that can be targeted in selected cases, suggesting that CUP represents a unique malignancy in which the genomic aberrations may be integral to the diagnosis. Recent trials focusing on tailored combination therapy matched to the genomic alterations in each cancer are providing new avenues of clinical investigation. Here, we discuss recent findings on molecular aberrations in CUP and how the genomic and immune landscape can be leveraged to optimize therapy. HighlightsCancer of unknown primary (CUP), by definition, is metastatic disease with an unidentifiable primary tumor.Patients with CUP are generally treated with empiric chemotherapies, such as taxanes and platinum-containing regimens; however, clinical outcomes remain poor.Recent studies with next-generation sequencing revealed that most CUP tumors harbored unique and complex genomic portfolios, with a mean of four to five alterations per tumor.CUP represents a unique cancer in which the genomic alterations may be the cornerstone of the diagnosis. Matched individualized combination targeted therapy in CUP merits prospective clinical investigation.