Go online to PeerView.com/MER860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Our understanding of the pathogenesis of GISTs was revolutionized by the discovery of KIT and PDGFRα mutations, which provided a diagnostic criteria and expanded treatment options. Tyrosine kinase inhibitors (TKIs), imatinib, sunitinib, and regorafenib are the recommended first three lines of therapy for most patients; however, tumor responses remain suboptimal, in part, because of resistance mutations associated with TKI therapy. With the goal to overcome treatment resistance and prolong life, research on modern TKIs has led to the approvals of avapritinib and ripretinib. Modern TKIs are also transforming the therapeutic algorithm for patients with unresectable/metastatic GISTs. In this video-based activity, leading experts on GISTs will dive into the pathobiology of this malignancy and discuss the latest data for newly approved and emerging agents to offer guidance on adopting modern targeted strategies to improve outcomes across multiple lines of therapy. Case vignettes and patient stories will help illustrate the practical aspects of multidisciplinary care throughout the treatment journey. Upon completion of this activity, participants should be better able to: Describe the pathobiology, including recurrence patterns and molecular/mutational features, of unresectable/metastatic GIST, Assess emerging and newly validated evidence on targeted TKI options for patients with GIST along multiple lines of treatment, Develop safe and effective therapeutic algorithms with modern TKIs based on molecular status, prior treatment history, and patient-centered factors, Plan management strategies associated with the use of modern TKIs in the GIST setting.