Gastrointestinal stromal tumors (GISTs) and leiomyosarcomas (LMSs) are common types of mesenchymal tumors that may present a diagnostic challenge. GISTs have frequent overexpression of Kit and often encode for mutation of the KIT oncogene. In addition, patients usually experience a favorable response to targeted therapy with imatinib mesylate (Gleevec, STI-571), but not cytotoxic chemotherapy. Up to 5% of GISTs can be completely negative for Kit on immunohistochemistry. Conversely, LMSs may rarely express Kit, but are virtually never associated with an activating KIT mutation, and are often effectively treated with cytotoxic chemotherapy but are resistant to imatinib. To aid in resolution of this clinical challenge, we performed a whole-genome gene expression study on 71 well-defined GIST and LMS samples with development of a robust, novel approach to molecular classification discussed herein.