GIST (gastrointestinal stromal tumor) are the most common mesenchymal tumors in gastrointestinal tract and are thought to derive from the cells of Cajal or their precursors that have a constitutional mutation in KIT and PDGFRA genes. There are KIT and PDGFRA genes mutations detected before the start of therapy that are believed to be related to GIST pathogenesis and some secondary mutations causing drug resistance and progression of disease. The most common KIT mutations are detected in exon 11 (66-71%), exon 9 (10-13%), exon 13,14,17 (1% each). PDGFRA mutations (8%) are described in exon 18 (5-6%), 12 (1%) and 14 (1%). No mutations are detected in 5-10% of tumors and those subtypes are called wild type GIST (WT). Imatinib mesilate is a selective inhibitor of KIT and PDGFRA with an antityrosine kinase activity (TKI) used in advanced or metastatic GIST as well as in adjuvant setting after complete resection of neoplasm. Imatinib has radically changed the therapy and prognosis of GIST, but sensitivity of the disease is different on the basis of leading mutations. GIST KIT exon 11 mutated manifests response rate in 80% of cases, exon 9 in 40% and GIST WT in 14%. PDGFRA shows a mild sensitivity to drug (66%) except the exon 18 D842 V mutation which is totally resistant. Unfortunately up to 15% of GIST have a primary resistance to imatinib that means progression of the disease within 6-12 months after the start of therapy. Another 40-50% of GIST develops a secondary resistance after >24 months of TKI treatment. Biopsy of progressing GIST shows multiple clonal origins with distinct mutational changes. Secondary resistance occurs almost exclusively in KIT mutated GIST with the appearances of T670I gatekeeper secondary mutation and less common in 14, 17, 18 exons. After progression of disease second line therapy is represented by sunitinib malate that overcomes the most common resistant mutations excepted PGDFRA D842V. Again, after few months of treatment, new different mutations appear and the disease progresses. Regorafenib is the third line therapy but too few data relates mutational status and regorafenib activity. In adjuvant setting only imatinib has a role. Two important studies (the USA ACOSOG Z 9001 and the German-Scandinavian study) fail to demonstrate that a specific mutation can predict a better DFS and OS in treated patients. On the contrary, volume of the tumor, number of mitosis and site of GIST are strong prognostic and predictive factors. In conclusion mutational analysis in GIST is at present more useful in metastatic setting than in adjuvant therapy. The insurgence of primary and secondary mutations during therapy is a fundamental step for disease progression.