Clinical management of patients with gastrointestinal stromal tumors (GISTs) has dramatically changed with the introduction of novel therapeutics, such as imatinib mesylate. This has created a need to re-evaluate the existing criteria used to assess treatment response. The current Response Evaluation Criteria in Solid Tumors are based on unidimensional tumor size, and do not take into account changes in responding GISTs such as a decrease in tumor density and decrease in the number of intratumoral vessels with computed tomography (CT). Positron emission tomography (PET) has been found to be highly sensitive in detecting early response, and to be useful in predicting long-term response to imatinib in patients with metastatic GIST; however, widespread use of PET is limited because of a lack of scanner availability and cost constraints. Modified CT criteria using a combination of tumor density and tumor size are promising in early response evaluation, and have excellent prognostic value. Identifying appropriate treatment response criteria is essential to optimize treatment for patients with GIST.