The spleen tyrosine kinase Syk was long thought to be a hematopoietic cell-specific signaling molecule. Recent evidence demonstrated that it is also expressed by many non-hematopoietic cell types and that it plays a negative role in cancer. A significant drop in its expression was first observed during breast cancer progression, but an anomalous Syk expression has now also been evidenced in many other tumor types. Mechanistic studies using Syk re-expression demonstrated its suppressive function in tumorigenesis and metastasis formation, which is surprising for a tyrosine kinase. Loss of Syk expression is regulated, albeit not exclusively, by its promoter hypermethylation. The molecular mechanism of its tumor-suppressive function remains largely unknown; the identification of its activators and effectors in non-hematopoietic cells will be a challenge for the years to come. An increasing number of clinical studies reveal a correlation between reduced Syk expression and an increased risk for metastasis formation, and assign Syk as a potential new prognostic marker in different tumor types.