Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in 
the digestive tract. In up to 90% of cases, they are characterized by activating 
mutations in the KIT or the PDGFRA gene. GIST represent a paradigm for 
successful targeted treatment with tyrosine kinase inhibitors (TKI). Since the 
approval of the TKI imatinib in 2002 the survival of patients with metastatic 
GIST has tripled. The next logical step was the concept of using imatinib in an 
adjuvant approach, which was recently shown to increase overall survival 
significantly. In both settings, the mutational status has high predictive 
implications. In detail, GIST with KIT exon 11 mutations show the best response 
rates with partial remission rates of up to 80%. In KIT exon 9 mutations, a 
doubled daily dose of 800 mg imatinib is now standard. The PDGFRA exon 18 
mutation D842V has been shown to lead to primary resistance. The treatment 
strategy in GIST is driven by their molecular characterisation. Further research 
has increased our knowledge on resistance mechanisms in solid tumors against 
TKI. The number of patients with secondary resistance due to acquired KIT 
mutations is increasing with treatment duration. Strategies to address this 
situation are the introduction of novel pathway inhibitors targeting different 
levels of signal transduction pathways, such as the mTOR/Akt pathway, the 
RAS/RAF pathway, histone deacetylation, among others. Among the GIST without 
mutations in the common hot spot regions of KIT and PDGFRA, the so-called 
wildtype GIST, further genomic subgroups have been identified. One such subgroup 
carries inactivating germline mutations in the genes encoding succinate 
dehydrogenase B, C, or D. They are associated with the occurrence of 
paragangliomas, so-called Carney-Stratakis syndrome. Most frequently, these GIST 
are located in the stomach, showing an epithelioid phenotype and a multinodular 
growth pattern. They preferentially occur in young females and often show lymph 
node metastases, the latter being very unusual in sporadic GIST. In sporadic 
Carney's triad additional pulmonary chondromas are observed and there are no SDH 
mutations. Another small subgroup of sporadic GIST present with BRAF mutations 
as an alternative genomic event. Finally, very rare kindreds with germline 
mutations in either KIT or PDGFRA have been described who develop multiple GIST 
and depending on the mutational subtype mastocytosis, hyperpigmentation and/or 
dysphagia. In summary, the molecular characterisation of GIST has revolutionized 
their treatment due to increasing knowledge about the high relevance of 
predictive molecular typing in solid tumors.