Gastrointestinal stromal tumours (GIST) predominantly express activating mutations of the KIT tyrosine kinase receptor and are successfully treated with imatinib mesylate, a KIT inhibitor. As resistance to imatinib causes therapy failure, our aim was to develop an in vivo GIST model to evaluate KIT inhibitors and monitor therapy with small animal positron emission tomography (PET). The first mouse model of GIST xenografts was successfully established by injecting GIST882 cells subcutaneously into nude mice. Using the small animal PET, FDG up-take in xenografts was significantly decreased after 24 h of treatment with imatinib, which correlated with a response to treatment, e.g., with a decrease in tumour volume, the inhibition of KIT and downstream intermediate phosphorylation and arrest of tumour cell proliferation as evaluated after 7 days of treatment. This model is useful to study imatinib resistance and to evaluate novel targeted therapies.