The mortality and morbidity of tumors of the upper GI tract are formidable with incidence and mortality nearly the same. Therefore, better therapies are necessary, and these are generally molecularly targeted therapies. This chapter focuses on the treatment of pancreatic cancer with targeted therapy. Important cellular pathways are reviewed, including signal transduction, proteasome inhibition, cell cycle, anti-angiogenesis pathways, immunologic therapies, viral therapy, epigenetic therapies and microarray analysis. Signal transduction pathways include epidermal growth factor receptors, such as cetuximab and Tarceva, as well as other less well-defined pathways. Proteasome inhibition includes inhibition of the 26S proteasome with PS-341. Cell cycle therapies include inhibitors of all the proteins involved in pushing the cell through the cell cycle. Viral therapies mainly cover the adenoviruses, like ONYX-015, and Reolysin, a type 3 serotype Dearing strain with little pathogenicity. Immunological therapies include cytokines, vaccines and cell-based therapies. Epigenetic therapies are mainly centered around histone deacetylases. Microarray analysis analyzes expression of thousands of genes to create a tumor profile, mainly for prognosis or prediction. Various promising treatment strategies are reviewed in terms of treatment with molecularly-guided therapies. Complications of therapy, particularly rash and thrombosis are reviewed.