The NTRK genes encode the tropomyosin-related receptor tyrosine kinases TrkA, TrkB and TrkC. TRK receptors play a critical role in the development of nervous system tissues during embryogenesis and early life. Recurrent genomic alterations in NTRK genes, typically fusions involving the 3′ region encoding the kinase domain juxtaposed to 5′ sequences from numerous partner genes, occur at a low frequency in a wide diversity of adult and pediatric cancers. Larotrectinib and entrectinib are potent first-generation NTRK inhibitors with IC50 in the nanomolar range in cellular contexts. Clinical trials of both drugs demonstrated significant and durable responses in patients with tumors harboring NTRK alterations, leading to first of its kind cancer agnostic FDA approvals in the United States for drugs targeting a genomic alteration. Unfortunately, acquired resistance inevitably develops. The second-generation NTRK inhibitors selitrectinib and repotrectinib are designed to overcome known mechanisms of resistance.