NTRK fusion-positive cancers are driven by oncogenic fusions of NTRK1, NTRK2, or NTRK3, which encode TRKA, TRKB, and TRKC, respectively. These fusions can be detected using DNA and RNA sequencing or plasma cell-free DNA profiling. First-generation TRK inhibitors like larotrectinib and entrectinib show high response rates (>75%) in patients with NTRK fusion-positive cancers, regardless of tumor histology. These inhibitors are well tolerated, though they can cause off-target adverse events. However, resistance to TRK inhibition can occur due to mutations in the NTRK kinase domain. Second-generation TRK inhibitors, such as LOXO-195 and TPX-0005, are being developed to overcome this resistance. The review discusses the biology of NTRK fusions, strategies to target these drivers, and the unique safety profile of TRK inhibitors. NTRK fusions are common in various cancers, including neuroblastoma, melanoma, and certain sarcomas. Diagnosis involves methods like NGS, FISH, and RT-PCR. TRK inhibitors like larotrectinib and entrectinib have shown significant clinical activity in clinical trials, with high response rates and durable disease control. Acquired resistance to TRK inhibition is often mediated by mutations in the TRK kinase domain, such as G595R and G623R. Next-generation TRK inhibitors are being developed to overcome these resistance mechanisms. TRK inhibition can lead to adverse effects due to the role of TRK proteins in various tissues, including the nervous system and cardiovascular system. Understanding these mechanisms is crucial for the safe and effective use of TRK inhibitors in cancer treatment.NTRK fusion-positive cancers are driven by oncogenic fusions of NTRK1, NTRK2, or NTRK3, which encode TRKA, TRKB, and TRKC, respectively. These fusions can be detected using DNA and RNA sequencing or plasma cell-free DNA profiling. First-generation TRK inhibitors like larotrectinib and entrectinib show high response rates (>75%) in patients with NTRK fusion-positive cancers, regardless of tumor histology. These inhibitors are well tolerated, though they can cause off-target adverse events. However, resistance to TRK inhibition can occur due to mutations in the NTRK kinase domain. Second-generation TRK inhibitors, such as LOXO-195 and TPX-0005, are being developed to overcome this resistance. The review discusses the biology of NTRK fusions, strategies to target these drivers, and the unique safety profile of TRK inhibitors. NTRK fusions are common in various cancers, including neuroblastoma, melanoma, and certain sarcomas. Diagnosis involves methods like NGS, FISH, and RT-PCR. TRK inhibitors like larotrectinib and entrectinib have shown significant clinical activity in clinical trials, with high response rates and durable disease control. Acquired resistance to TRK inhibition is often mediated by mutations in the TRK kinase domain, such as G595R and G623R. Next-generation TRK inhibitors are being developed to overcome these resistance mechanisms. TRK inhibition can lead to adverse effects due to the role of TRK proteins in various tissues, including the nervous system and cardiovascular system. Understanding these mechanisms is crucial for the safe and effective use of TRK inhibitors in cancer treatment.