NTRK gene fusions involving NTRK1, NTRK2, or NTRK3 are oncogenic drivers in various adult and pediatric cancers. These fusions can be detected using various methods, including tumor DNA and RNA sequencing and plasma cell-free DNA profiling. First-generation TRK inhibitors, such as larotrectinib and entrectinib, have shown high response rates (>75%) in patients with NTRK fusion-positive cancers, regardless of tumor histology. These inhibitors are well tolerated, with occasional off-tumor, on-target adverse events. However, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition, often due to the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors like LOXO-195 and TPX-0005, which are currently being explored in clinical trials. This review discusses the biology of NTRK fusions, strategies to target these drivers in both treatment-naive and acquired resistance settings, and the unique safety profile of TRK inhibitors.NTRK gene fusions involving NTRK1, NTRK2, or NTRK3 are oncogenic drivers in various adult and pediatric cancers. These fusions can be detected using various methods, including tumor DNA and RNA sequencing and plasma cell-free DNA profiling. First-generation TRK inhibitors, such as larotrectinib and entrectinib, have shown high response rates (>75%) in patients with NTRK fusion-positive cancers, regardless of tumor histology. These inhibitors are well tolerated, with occasional off-tumor, on-target adverse events. However, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition, often due to the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors like LOXO-195 and TPX-0005, which are currently being explored in clinical trials. This review discusses the biology of NTRK fusions, strategies to target these drivers in both treatment-naive and acquired resistance settings, and the unique safety profile of TRK inhibitors.