Colorectal cancer (CRC) is a common and heterogeneous disease that arises from the accumulation of genetic mutations. Recent advances in genomic medicine have improved understanding of its molecular basis, leading to the development of targeted therapies tailored to individual tumour mutations. This review outlines the current understanding of the molecular genetics of CRC, focusing on the adenoma-carcinoma sequence, genomic instability, and key genetic mutations involved in CRC development. CRC arises from the accumulation of genetic and epigenetic mutations, transforming normal cells into benign adenomas and eventually into invasive carcinomas. The adenoma-carcinoma sequence is a key pathway in CRC development, with serrated adenomas also having the potential for malignant transformation. Genomic instability, including chromosomal instability (CIN), microsatellite instability (MSI), aberrant DNA methylation, and DNA repair defects, plays a critical role in CRC progression. Key genes involved in CRC tumourigenesis include APC, MLH1, MSH2, MSH6, PMS2, and TP53, with mutations in these genes leading to loss of function and uncontrolled cell growth. Familial adenomatous polyposis (FAP) is an autosomal dominant condition caused by germline mutations in the APC gene, leading to the development of numerous colonic polyps and a high risk of CRC. Lynch syndrome, caused by germline mutations in MMR genes, is the most common hereditary CRC syndrome, with a high lifetime risk of CRC and increased risk of extracolonic malignancies. Aberrant DNA methylation and mutations in the MYH gene are also associated with CRC development. Oncogenes such as KRAS and PI3K are involved in CRC progression, with KRAS mutations being associated with resistance to anti-EGFR therapy. Genetic testing for KRAS mutations is important in determining the suitability of targeted therapies such as cetuximab in the treatment of metastatic CRC. The introduction of targeted therapies has significantly impacted the management of metastatic CRC, with cetuximab showing efficacy in patients with KRAS wild-type tumours. Overall, the molecular basis of CRC is complex and heterogeneous, with a range of genetic mutations contributing to its development. Understanding these genetic mechanisms is essential for the development of targeted therapies and improved patient outcomes.Colorectal cancer (CRC) is a common and heterogeneous disease that arises from the accumulation of genetic mutations. Recent advances in genomic medicine have improved understanding of its molecular basis, leading to the development of targeted therapies tailored to individual tumour mutations. This review outlines the current understanding of the molecular genetics of CRC, focusing on the adenoma-carcinoma sequence, genomic instability, and key genetic mutations involved in CRC development. CRC arises from the accumulation of genetic and epigenetic mutations, transforming normal cells into benign adenomas and eventually into invasive carcinomas. The adenoma-carcinoma sequence is a key pathway in CRC development, with serrated adenomas also having the potential for malignant transformation. Genomic instability, including chromosomal instability (CIN), microsatellite instability (MSI), aberrant DNA methylation, and DNA repair defects, plays a critical role in CRC progression. Key genes involved in CRC tumourigenesis include APC, MLH1, MSH2, MSH6, PMS2, and TP53, with mutations in these genes leading to loss of function and uncontrolled cell growth. Familial adenomatous polyposis (FAP) is an autosomal dominant condition caused by germline mutations in the APC gene, leading to the development of numerous colonic polyps and a high risk of CRC. Lynch syndrome, caused by germline mutations in MMR genes, is the most common hereditary CRC syndrome, with a high lifetime risk of CRC and increased risk of extracolonic malignancies. Aberrant DNA methylation and mutations in the MYH gene are also associated with CRC development. Oncogenes such as KRAS and PI3K are involved in CRC progression, with KRAS mutations being associated with resistance to anti-EGFR therapy. Genetic testing for KRAS mutations is important in determining the suitability of targeted therapies such as cetuximab in the treatment of metastatic CRC. The introduction of targeted therapies has significantly impacted the management of metastatic CRC, with cetuximab showing efficacy in patients with KRAS wild-type tumours. Overall, the molecular basis of CRC is complex and heterogeneous, with a range of genetic mutations contributing to its development. Understanding these genetic mechanisms is essential for the development of targeted therapies and improved patient outcomes.