Colorectal cancer is one of the most frequent malignant tumors with a still increasing incidence in Western countries. Currently, colorectal cancer is the second most common cancer in Europe both in terms of incidence and mortality. Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. Thus, metastasis is the most lethal attribute of colorectal cancer. Today, colorectal cancer and metastasis thereof are understood as the results of early changes during tumor progression that determine the metastasis capacity. Much is known about molecules contributing to the metastasis phenotype, the pathways they control, and the genes they regulate. However, patient prognosis is mainly defined by histopathological staging, a static description of the anatomical extent of tumor spread within a surgical specimen. This review demonstrates the need for and possibilities of molecular-based staging as an essential prerequisite for improved diagnosis, prognosis, and therapy. Molecular determinants for progression and metastasis of colorectal cancer are discussed representing both potential markers for metastasis prognosis and targets for intervention strategies aiming at the ultimate goal of metastasis prevention.