The prognosis of patients with a GIST improved significantly since the introduction of imatinib mesylate treatment, leading to disease control in 70% to 85% of patients. The response depends on the presence/ absence and type of mutations in the KIT or Platelet derived growth factor receptor. Unfortunately, we are increasingly faced with the problem of resistance to imatinib treatment, mainly secondary resistance, which by definition occurs after at least 6 months of initial response to the drug. The effects of imatinib on a GIST are still in full exploration and this review focuses upon the available data on the phenotype and genotype of a GIST treated with imatinib. Two settings are elaborated separately, a responding/stable GIST, and a resistant GIST. In addition, the attention will be drawn to remarkable (immuno)phenotypic changes that can occur in a GIST under imatinib treatment.