This review provides an overview of the molecular genetics of colorectal cancer (CRC), a common but heterogeneous disease that arises through the accumulation of genetic mutations. The article highlights the rapid advancements in genomic medicine, which have led to the development of targeted therapies and the potential for personalized treatment regimens based on individual tumor mutation profiles. Understanding the pathological mechanisms driving CRC is crucial for gastroenterologists to effectively manage the disease. The review begins by introducing CRC as the third most common malignancy in the UK, with a high lifetime risk for both men and women. It emphasizes that CRC is not a single entity but a group of diseases influenced by various molecular pathways, affecting susceptibility to cancer and responsiveness to antitumor agents. The adenoma-carcinoma sequence, where benign adenomas progress to invasive carcinomas, is a key concept. The National Polyp Study in the USA provided evidence for the importance of removing adenomatous polyps at colonoscopy to reduce the incidence of CRC. The review then delves into the mechanisms of genomic instability, including chromosomal instability (CIN), microsatellite instability (MSI), aberrant DNA methylation, and DNA repair defects. These instability forms facilitate the acquisition of multiple mutations that drive CRC development. Specific genes involved in these processes, such as APC, MLH1, MSH2, and MYH, are discussed, along with their roles in CRC pathogenesis. The article also covers inherited syndromes like familial adenomatous polyposis (FAP) and Lynch syndrome, which are characterized by germline mutations leading to increased risk of CRC. Genetic testing for these syndromes is highlighted as a critical tool for targeted surveillance and management. Finally, the review explores oncogenic mutations in pathways such as the epidermal growth factor receptor (EGFR), mitogen-associated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K), which can lead to loss of cellular regulation and cancer development. The success of targeted therapies, such as cetuximab for KRAS wild-type metastatic CRC, is discussed, along with the potential for future advancements in molecular techniques to improve diagnosis, risk stratification, and management of CRC.This review provides an overview of the molecular genetics of colorectal cancer (CRC), a common but heterogeneous disease that arises through the accumulation of genetic mutations. The article highlights the rapid advancements in genomic medicine, which have led to the development of targeted therapies and the potential for personalized treatment regimens based on individual tumor mutation profiles. Understanding the pathological mechanisms driving CRC is crucial for gastroenterologists to effectively manage the disease. The review begins by introducing CRC as the third most common malignancy in the UK, with a high lifetime risk for both men and women. It emphasizes that CRC is not a single entity but a group of diseases influenced by various molecular pathways, affecting susceptibility to cancer and responsiveness to antitumor agents. The adenoma-carcinoma sequence, where benign adenomas progress to invasive carcinomas, is a key concept. The National Polyp Study in the USA provided evidence for the importance of removing adenomatous polyps at colonoscopy to reduce the incidence of CRC. The review then delves into the mechanisms of genomic instability, including chromosomal instability (CIN), microsatellite instability (MSI), aberrant DNA methylation, and DNA repair defects. These instability forms facilitate the acquisition of multiple mutations that drive CRC development. Specific genes involved in these processes, such as APC, MLH1, MSH2, and MYH, are discussed, along with their roles in CRC pathogenesis. The article also covers inherited syndromes like familial adenomatous polyposis (FAP) and Lynch syndrome, which are characterized by germline mutations leading to increased risk of CRC. Genetic testing for these syndromes is highlighted as a critical tool for targeted surveillance and management. Finally, the review explores oncogenic mutations in pathways such as the epidermal growth factor receptor (EGFR), mitogen-associated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K), which can lead to loss of cellular regulation and cancer development. The success of targeted therapies, such as cetuximab for KRAS wild-type metastatic CRC, is discussed, along with the potential for future advancements in molecular techniques to improve diagnosis, risk stratification, and management of CRC.