Sarcomas are rare malignancies of mesenchymal lineage with more than 100 specific types and many benign potential mimics. In situ and precursor lesions are generally not described and thus much of molecular pathology in this field concentrates on molecular diagnosis, prognosis and determination of therapeutic targets. This chapter discusses the applications of molecular methodologies that provide insight into pathogenesis of sarcoma, and of molecular methods which are currently applied to, or will likely soon influence, the clinical management of this complex array of tumors.