Fibroblast activation protein-α (FAP) is a type II transmembrane serine protease with extensive endonuclease activity that is almost undetectable in normal tissues. In contrast, it is particularly pronounced in a wide range of cancers, and an increased level of FAP is often associated with worse clinical outcomes. Here, we summarize and discuss the basic introduction of FAP, its biological features, and recent advances in understanding the role and clinical significance of FAP in a variety of cancers. In addition, the enzymatic activities of FAP and its different substrates, its nonenzymatic activities, and the key role in regulating different signaling pathways are reviewed. Finally, the high tremendous potential of FAP as an effective therapeutic target for the management of different inflammatory and oncologic conditions has been investigated.