The aims of this review are to: 1) systematically analyze current literature and perform a meta-analysis of the available data on the impact of key genetic variants in CRC-related genes (i.e., KRAS, NRAS, BRAF, SMAD4, PIK3CA) as prognostic markers in surgically treated metastatic CRC patients; and 2) explore the potential role of emerging biomarkers like HER2 and microsatellite instability (MSI) status in current and novel therapeutic strategies, including liver transplantation for LM. Here, SMAD4 is linked to colorectal carcinoma.