Skeletal metastases of unknown primary present a diagnostic and therapeutic challenge for clinicians. The origin of the primary cancer is unobtainable in 3–5% of cancer patients, leading to poorer outcomes, with median overall survival ranging from 3 to 12 months, and one-year survival rates as low as 14.5%. For this reason, all possible methods of evaluation and diagnostic testing should be pursued in a stepwise manner. We outline a systematic diagnostic approach starting with a thorough history and physical examination, followed by common laboratory testing including a complete blood count and metabolic panel, with tumor markers, such as a prostate-specific antigen and carcinoembryonic antigen. Advanced imaging modalities are crucial, starting with determining the characteristics of the skeletal metastases on a plain radiograph, followed by bone scans, CT, MRI, and PET/CT. Tissue biopsy with immunohistochemistry remains the gold standard for diagnosis with molecular profiling and next-generation sequencing offering additional insights. The management of bone or muscle metastasis of unknown primary is typically palliative, with the main goal being symptom control, prolongation of survival, and improvement in quality of life. Systemic therapies, including chemotherapy, targeted agents, immunotherapies, and local therapies, such as radiation or surgery are utilized in a multidisciplinary manner. This chapter emphasizes the importance of early diagnosis while describing different modalities available to determine cancer origins in this challenging patient population.