Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These form a distinct category of tumors characterized by oncogenic mutations of the KIT receptor tyrosine kinase in a majority of patients. KIT is used not only for diagnosis but also for targeted therapy of GISTs. Imatinib, a tyrosine kinase inhibitor, is widely used in the treatment of advanced and metastatic GISTs and has been recently employed in the neo adjuvant and adjuvant set-up with encouraging results. Certain specific mutations in an exon (such as in exon 9) of the KIT gene result in GISTs that are relatively unresponsive to the Imatinib treatment. New therapeutic agents like Sunitinib have now been approved for the treatment of Imatinib-resistant GIST. This review summarizes the salient features of GIST along with a detailed review of targeted multi-disciplinary approach to the treatment of these special tumors.