Imaging technology plays a major role in treatment response assessment in solid tumors and in surveillance for recurrence or progression. Currently available response evaluation criteria, Response Evaluation Criteria in Solid Tumors (RECIST), are based on unidimensional tumor size. Recently, however, these strictly size-based criteria for evaluating responses have been criticized because they do not reflect the biologic changes of solid tumors induced by targeted therapies and thus may be misleading. This problem is evident in response evaluation in advanced gastrointestinal stromal tumor (GIST) treated with a new molecularly targeted agent, imatinib. GISTs can increase in size despite good response to imatinib, and focal progression within a responding GIST can be overlooked with current size-based imaging criteria. Modified objective criteria using a combination of tumor size and density on CT are promising in early response evaluation and in predicting long-term prognosis in patients with advanced GIST treated with imatinib. These criteria may have broad applicability as additional targeted therapies become available to treat solid tumors.