FES (feline sarcoma oncogene) and Fer are the only two members of a unique family of cytoplasmic protein tyrosine kinases. FES and Fer contain a central Src homology-2 (SH2) domain and a carboxy-terminal tyrosine kinase catalytic domain. They are structurally distinguished from other members of cytoplasmic protein tyrosine kinase subfamilies by the presence of amino-terminal Fer/CIP4 homology and coiled-coil domains. FES was originally identified as an oncogene from avian and feline retroviruses. Human c-Fes has been implicated in myeloid, vascular endothelial and neuronal cell differentiation. FES has tyrosine-specific protein kinase activity and that activity is required for maintenance of cellular transformation. Mutations may activate the FES kinase and thereby contribute to cancer. However, recent data strongly suggests that the c-FES protein-tyrosine kinase is a tumor suppressor rather than a dominant oncogene in colorectal cancer.