Prognosis and clinical management of patients with gastrointestinal stromal tumors (GIST) has changed significantly with the introduction of new molecular-targeted drugs such as imatinib. This development is accompanied by a need to re-evaluate the established imaging criteria used to assess treatment response. The frequently used response evaluation criteria in solid tumors (RECIST) are mainly based on one-dimensional tumor size and do not take into account functional changes in responding GISTs such as a decrease in CT density or in the number of intratumoral vessels. Positron emission tomography (PET) has been found to be highly sensitive in detecting early response and to have a predictive value in the long term response to imatinib treatment. Monitoring the course of the disease by PET is limited due to scanner availability and economic constraints. Modified CT response criteria using a combination of tumor density and tumor size are especially promising in early response assessment and have a good prognostic value. Further optimization of existing response criteria and evaluation of new candidate markers of treatment response, such as quantitative perfusion will be the key for optimized monitoring of targeted therapies in GIST.