Cardiovascular-kidney-metabolic (CKM) syndrome is a complex interplay of metabolic dysregulation, renal dysfunction, and cardiovascular disease, linked by molecular and pathophysiological pathways. As the understanding of molecular mechanisms advances, the recognition of the role of genetic predisposition becomes more prominent. This chapter provides a selective review of the current state of knowledge on the genetic basis of CKM, highlighting key genetic loci, pathways, and their phenotypical implications. Many polymorphisms in genes that encode proteins involved in different cellular pathways and epigenetic factors contribute to CKM components and progression. Future genetic studies are required to identify the key genetic factors that connect the complex mechanisms. A polygenic risk score could summarize genetic predisposition and increase prediction accuracy. Although monogenic disorders are rare, a significant proportion of patients with CKM have a purely genetic condition, and early diagnosis is essential for prognosis and genetic counselling. Genetic testing in CKM syndrome has become a means to assess risk, inform personalized treatments, and enhance early detection.