Skeletal metastases of unknown primary (SMUP) represent a clinical challenge in dealing with patients diagnosed with bone metastases. Management of these patients has improved significantly in the past few years. however, it is fraught with a lack of evidence. While some patients have achieved impressive gains, a more systematic and tailored treatment is required. Nevertheless, in real-life practice, the outlook at the beginning of treatment for SMUP is decidedly somber. An incomplete translational relevance of pathological and clinical data on the mortality and morbidity rate has had unsatisfactory consequences for SMUP patients and their physicians. We examined several approaches to confront the available evidence; three key points emerged. The characterization of the SMUP biological profile is essential to driving clinical decisions by integrating genetic and molecular profiles into a multi-step diagnostic work-up. Nonetheless, a pragmatic investigation plan and therapy of SMUP cannot follow a single template; it must be adapted to different pathophysiological dynamics and coordinated with efforts of a systematic algorithm and high-quality data derived from statistically powered clinical trials. The discussion in this review points out that greater efforts are required to face the unmet needs present in SMUP patients in oncology.