Abstract: Tyrosine kinase inhibitors (TKIs), such as imatinib, are the backbone for advanced gastrointestinal stromal tumor (GIST) treatment, which significantly improves patients’ prognosis. However, the management of acquired drug resistance mutations following multiple-line therapies remains inadequate. Recently, ripretinib and avapritinib have been serving as more therapeutic choices and have been included in the current clinical guidelines for advanced GIST treatment. Concurrently, there are also some other targeted therapies based on different mechanisms, which have entered phase I clinical trials and shown potential efficacy and safety (HQP1351, binimetinib, DS-6157a, and immunotherapy combined with traditional targeted drugs). Therefore, this review aims to summarize the current state and trend of phase I clinical trials of new drugs in GIST treatment. The move into a new era on the treatment of GIST with more in-depth studies on GIST pathological mechanisms and development of new potent TKIs and other agents will be promising.