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Gastrointestinal stromal tumors (GISTs), the most common mesenchymal neoplasms of the gastrointestinal tract, are molecularly heterogeneous diseases rather than a single entity. Activating mutations in KIT and PDGFRA define the dominant biological dependencies and establish tyrosine kinase inhibition as a therapeutic backbone. Imatinib, followed by later-line tyrosine kinase inhibitors, including sunitinib, regorafenib, ripretinib, and genotype-selected avapritinib, have substantially prolonged survival. However, durable disease control remains limited by clonal evolution, most notably, polyclonal secondary KIT mutations and lesion-to-lesion molecular heterogeneity. Molecular profiling using serial tissue and circulating tumor DNA analyses may improve precision care by identifying spatially and temporally evolving resistance mechanisms and guiding mutation-matched treatment selection. In this review, we summarize the biological and molecular landscape of advanced GIST, as well as the current therapeutic strategies and major mechanisms of resistance. Finally, we highlight promising therapeutic strategies supported by preclinical and clinical evidence that may advance subtype-informed precision medicine.