Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, with approximately 85% to 90% driven by mutations in the KIT or platelet derived growth factor receptor α (PDGFRA) genes. Although surgical resection is the preferred treatment for localized GIST, molecular targeted therapy has become the mainstay for unresectable or metastatic/recurrent GIST. Imatinib, the first-line standard therapeutic agent, has significantly improved patient outcomes; however, nearly all patients eventually develop resistance, leading to disease progression. Second-line therapy with sunitinib and third-line therapy with regorafenib can modestly extend progression-free survival (PFS), but their overall effectiveness remains limited. Ripretinib, a novel broad-spectrum KIT/PDGFRA inhibitor, exerts its antitumor effects through a unique dual mechanism of action—simultaneously inhibiting kinase activation loop and switch pocket mutations—and has significantly prolonged PFS in patients with advanced GIST. It has also become the first drug globally approved for fourth-line treatment. Nevertheless, clinical practice has shown that secondary resistance to ripretinib still occurs, leading to disease progression and severely compromising long-term therapeutic efficacy. This article systematically reviews the pharmacological mechanisms of ripretinib in treating GIST, the key signaling pathways associated with resistance, and the latest research advances in therapeutic strategies targeting resistance, aiming to provide both theoretical and practical references for optimizing clinical treatment regimens.