Primary cutaneous sarcomas account for 14% of all sarcomas [1]. Partly owing to their relative rarity, diagnosis of these tumors is often challenging. All too often a pathologist is faced with a small biopsy, and has to differentiate a common benign mesenchymal tumor from its malignant counterpart, or classify a malignant tumor based on a limited tissue sample. Fortunately, basic science discoveries over the last several decades have demonstrated that many benign and malignant mesenchymal tumors of the skin have characteristic genetic changes. This chapter will discuss how adjunct molecular genetic testing can be used in the diagnosis and prognostication of these lesions, and in directing patient therapy.