The TRK A, B, and C proteins, encoded by the NTRK1, 2, and 3 genes, are preferentially expressed in tissues of neural origin and play a role in the regulation of cell differentiation and survival. Several isoforms of the three TRK proteins exist. NTRK1, 2, and 3 are oncogenes that can be activated and drive cancer progression when chromosomal rearrangements lead to their aberrant juxtaposition with other genes. The resulting overexpressed and constitutively active TRK fusion proteins are responsible for aberrant signaling through downstream pathways. NTRK fusion proteins are expressed in a wide range of commonly occurring tumors, such as lung cancer, thyroid cancer, and sarcoma at low frequency. Wild-type TRK protein expression has a rather low prevalence in most solid tumors but can be substantial in some neuroendocrine tumor tissues.