Mesenchymal neoplasia presents numerous challenges to pathologic classification. Histologic features can be deceiving, and traditional immunohistochemical markers of differentiation may be of little use in narrowing the diagnosis. Fortunately, great strides have been made in unraveling the genetic and genomic alterations associated with both sarcomagenesis and benign neoplasia. In turn, these advances have led to an expansion of the available diagnostic toolkit for sarcoma pathology. In order to assist the practicing pathologist in integrating these tools into their repertoire, this article will discuss some of the latest advances in sarcoma diagnosis, including an update on translocation-associated sarcomas, and will review a number of sarcoma-specific immunohistochemical studies developed over the past decade. Some of the potential uses and pitfalls of commonly used tests will be addressed. Finally, the discussion will briefly touch upon the impact that advances in molecular technologies, particularly targeted gene expression analysis, may have on altering the face of diagnostic pathology.