Musculoskeletal metastases significantly impact patient morbidity and mortality, with bone and soft tissue sarcomas (STSs) exhibiting distinct pathophysiological mechanisms compared to carcinomas. While carcinomas, which arise from epithelial tissues, primarily spread via the lymphatic system and target the axial skeleton, sarcomas originate from mesenchymal tissues and metastasize predominantly through hematogenous routes, commonly affecting the lungs, bones, and soft tissues. The metastatic cascade in both tumor types involves key molecular processes, including epithelial-to-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and immune system evasion, but sarcomas display unique biological behaviors due to their mesenchymal origin. Compared to carcinomas, which often exhibit well-characterized oncogenic mutations such as KRAS and TP53, sarcomas display a more heterogeneous genetic landscape, including chromosomal translocations and complex karyotypic abnormalities. This biological variability has posed challenges for treatment, but recent advancements in molecular profiling have identified novel therapeutic targets. Emerging strategies, such as tyrosine kinase inhibitors, immune checkpoint inhibitors, and agents targeting sarcoma-specific pathways, offer promising avenues to improve outcomes. By elucidating the distinct pathophysiology of sarcomas versus carcinomas, this chapter provides a foundation for the development of targeted interventions aimed at mitigating metastatic disease and enhancing patient survival.