Abstract Background and objectives. The introduction of targeted therapies has led to improved clinical outcomes in patients with unresectable gastrointestinal stromal tumours (GIST). The receptor tyrosine kinase (RTK) inhibitor imatinib mesylate has been approved as the first-line choice of therapy for this group of patients, while the RTK inhibitor, sunitinib malate, has been approved for the treatment of GIST after disease progression or intolerance to imatinib. Here we discuss and compare the tolerability profiles of imatinib and sunitinib based on published clinical trial data. We also review available data on the potential mechanisms by which these agents may cause adverse events (AEs) and we propose some general strategies to help clinicians to optimise treatment benefit with these agents. Findings. While the toxicity profiles of imatinib and sunitinib are well known, the mechanisms of toxicity of these agents have yet to be elucidated fully. Clinical observations along with retrospective and prospective analyses suggest that some RTK inhibitor-related AEs have a higher incidence than previously reported from clinical trials. In addition, with greater use, new and unexpected AEs are emerging. Clinicians need to be familiar with the toxicity profiles of RTK inhibitors as well as individual patient risk factors in order to optimise treatment benefit. Conclusions. Imatinib and sunitinib are generally well tolerated with known and manageable AE profiles. Proactive therapy management strategies can enable treatment optimisation and allow patients to continue treatment with minimal interruption.