Colon cancer is still the second most frequent malignancy in the Western world. Despite major efforts in diagnosis and treatment it is one of the leading causes of cancer related deaths. The metastatic dissemination of primary tumors is directly linked to patient's survival and accounts for about 90% of all colon cancer deaths. Current clinical predictions on whether colon cancer will metastasize are mainly defined by histopathological staging, describing the tumor spread within a surgical specimen. This review focuses on the need for molecule-based staging as essential prerequisite for individualized diagnosis, prognosis and therapy. Molecular determinants for progression and metastasis of colon cancer are discussed. Moreover, a newly identified molecule playing a decisive role in colon cancer metastasis is highlighted: MACC1. MACC1 acts as a key regulator of the metastasis-inducing HGF/Met pathway, predicts the risk for metastasis in early cancer stages, and represents a novel target to attack metastasis.