Tropomyosin-related kinases (Trks) are receptor tyrosine kinases (RTK class VII, Trk receptor family) normally expressed in neuronal tissue where they play important role in both development and function of the nervous system. The Trk receptor family is composed of three members (A, B, and C) activated by specific ligands called neurotrophins (NTs). Activations upon ligand binding triggers oligomerization of the receptors, phosphorylation of specific tyrosine residues in the kinase domain, and downstream signal transduction pathways, including survival, proliferation, and differentiation in normal and neoplastic neuronal cells. Deregulation of TrkA and TrkB and their cognate ligands has been described in numerous types of cancers including prostate, breast, colorectal, ovarian, lung, pancreas, melanoma, thyroid, and neuroblastoma and occurs mainly through wild type receptor overexpression, activation, amplification, and/or mutation. Importantly, increased Trks activation in tumor tissues correlates with an aggressive phenotype and poor clinical outcome.