Musculoskeletal metastases are common in oncology patients and often require biopsy for diagnosis, treatment planning, and molecular profiling. We outline how to best obtain lesional tissue, focusing on percutaneous image-guided biopsy as the preferred approach due to its minimally invasive nature. We detail appropriate indications, planning considerations, imaging modalities, biopsy techniques, and strategies to optimize diagnostic yield while minimizing complications and preserving future surgical options. While a core needle biopsy (CNB) is usually sufficient, an open surgical biopsy remains an option for inconclusive cases. Ultimately, properly performed biopsies are crucial for accurate diagnosis and effective treatment of musculoskeletal lesions and are best handled by experienced teams coordinating care in specialized centers.