Tropomyosin receptor kinases (TRKs) were first identified in 1986 when NTRK1 was discovered as part of an oncogenic fusion gene in colorectal cancer and the discovery of NTRK2 and NTRK3 followed shortly after. In the decades since their discovery, TRKs have been implicated in a number of cancer types due to their canonical roles in promoting cell proliferation and survival. Studies have shown that increased expression and/or activity of TRKs can be indicative of metastatic potential, suggesting that TRKs can be therapeutic targets in aggressive cancers. While predominantly known for forming oncogenic gene fusions, aberrant alternative splicing does not appear to be a prerequisite for TRK-mediated metastasis. However, expression and activity of each TRK can confer either a pro-apoptotic or pro-survival effect in different tissue types, predicting a complex treatment paradigm for patients exhibiting abnormalities in TRK expression or activity. While preclinical studies on TRK kinases continue, clinical advances in TRK inhibition were achieved upon Larotrectinib (Vitrakvi) becoming the first FDA-approved pan-TRK inhibitor. This review summarizes findings regarding TRK expression and activity in different tissue types, the biological impact of aberrant TRK signaling, and the potential for additional inhibitor design.