Uncontrollable metastatic outgrowth process is the leading cause of mortality worldwide, even in the case of colorectal cancer. Colorectal cancer (CRC) accounts for approximately 10% of all annually diagnosed cancers and 50% of CRC patients will develop metastases in the course of disease. Most patients with metastatic CRC have incurable disease. Even if patients undergo resection of liver metastases, the 5-year survival rate ranges from 25 to 58%. Next-generation sequencing of tumour specimens from large colorectal cancer patient cohorts has led to major advances in elucidating the genomic landscape of these tumours and paired metastases. The expression profiles of primary CRC and their metastatic lesions at both the gene and pathway levels were compared and led to the selection of early driver genes responsible for carcinogenesis and metastasis-specific genes that increased the metastatic process. The genetic, transcriptional and epigenetic alteration encoded by these genes and their combination influence many pivotal signalling pathways, enabling the dissemination and outgrowth in distant organs. Therapeutic regimens affecting several different active pathways may have important implications for therapeutic efficacy.