The Renin–Angiotensin System and Cardiovascular–Kidney–Metabolic Syndrome: Focus on Early-Life Programming The Renin–Angiotensin System (RAS) plays a critical role in maternal–fetal health and maintaining homeostasis in cardiovascular, metabolic, and kidney functions. This review highlights the role of RAS in the early-life programming of cardiovascular–kidney–metabolic (CKM) syndrome, focusing on how RAS dysregulation during pregnancy and lactation leads to CKM characteristics in offspring. The RAS influences fetal programming and triggers CKM traits in offspring, suggesting it as a promising reprogramming strategy. The review also presents interventions targeting the RAS to prevent CKM traits. The RAS is a hormonal cascade that begins with the expression of angiotensinogen (AGT), which is converted into angiotensin (Ang) I by the renin enzyme. Ang I is then cleaved into Ang II by angiotensin-converting enzyme (ACE). The RAS plays a pivotal role in orchestrating various physiological functions within the cardiovascular system, kidneys, and metabolic homeostasis. Ang II induces vasoconstriction and cell proliferation, contributing to conditions such as hypertension, chronic kidney disease (CKD), obesity, liver steatosis, and diabetes. The non-classical RAS pathway, involving the ACE2-ANG-(1-7)-MAS receptor axis, counterbalances the detrimental effects of Ang II signaling. The RAS is involved in the development of CKM syndrome, which is characterized by the interplay between metabolic disorders, kidney ailments, and cardiovascular conditions. Early-life exposure to unfavorable environmental factors can trigger abnormal RAS activation, leading to CKM syndrome in later life. The RAS is also involved in the development of various diseases, including cardiovascular disease, kidney disease, obesity, diabetes, and dyslipidemia. The RAS is influenced by various factors, including maternal nutrition, illnesses, and chemical exposures, which can lead to CKM syndrome in offspring. Animal models have been used to investigate the programming of the RAS and its impact on the cardiovascular, kidney, and metabolic health of offspring. These models include maternal nutritional imbalance, maternal illnesses and conditions, and drug and chemical exposures. The RAS is a key target for reprogramming interventions to prevent CKM syndrome. Current interventions targeting the RAS include renin inhibitors, ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), AT1R antisense, and ACE2 activators. These interventions have shown protective effects against CKM traits, including hypertension, kidney disease, and cardiovascular disease. The review emphasizes the need for further research to develop optimal methodologies for understanding the RAS and ensuring that RAS-based therapy is directed appropriately. It also highlights the importance of determining the optimal dosage in a sex-dependent manner to maximize benefits without increasing toxicity before clinical translation. The review provides valuableThe Renin–Angiotensin System and Cardiovascular–Kidney–Metabolic Syndrome: Focus on Early-Life Programming The Renin–Angiotensin System (RAS) plays a critical role in maternal–fetal health and maintaining homeostasis in cardiovascular, metabolic, and kidney functions. This review highlights the role of RAS in the early-life programming of cardiovascular–kidney–metabolic (CKM) syndrome, focusing on how RAS dysregulation during pregnancy and lactation leads to CKM characteristics in offspring. The RAS influences fetal programming and triggers CKM traits in offspring, suggesting it as a promising reprogramming strategy. The review also presents interventions targeting the RAS to prevent CKM traits. The RAS is a hormonal cascade that begins with the expression of angiotensinogen (AGT), which is converted into angiotensin (Ang) I by the renin enzyme. Ang I is then cleaved into Ang II by angiotensin-converting enzyme (ACE). The RAS plays a pivotal role in orchestrating various physiological functions within the cardiovascular system, kidneys, and metabolic homeostasis. Ang II induces vasoconstriction and cell proliferation, contributing to conditions such as hypertension, chronic kidney disease (CKD), obesity, liver steatosis, and diabetes. The non-classical RAS pathway, involving the ACE2-ANG-(1-7)-MAS receptor axis, counterbalances the detrimental effects of Ang II signaling. The RAS is involved in the development of CKM syndrome, which is characterized by the interplay between metabolic disorders, kidney ailments, and cardiovascular conditions. Early-life exposure to unfavorable environmental factors can trigger abnormal RAS activation, leading to CKM syndrome in later life. The RAS is also involved in the development of various diseases, including cardiovascular disease, kidney disease, obesity, diabetes, and dyslipidemia. The RAS is influenced by various factors, including maternal nutrition, illnesses, and chemical exposures, which can lead to CKM syndrome in offspring. Animal models have been used to investigate the programming of the RAS and its impact on the cardiovascular, kidney, and metabolic health of offspring. These models include maternal nutritional imbalance, maternal illnesses and conditions, and drug and chemical exposures. The RAS is a key target for reprogramming interventions to prevent CKM syndrome. Current interventions targeting the RAS include renin inhibitors, ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), AT1R antisense, and ACE2 activators. These interventions have shown protective effects against CKM traits, including hypertension, kidney disease, and cardiovascular disease. The review emphasizes the need for further research to develop optimal methodologies for understanding the RAS and ensuring that RAS-based therapy is directed appropriately. It also highlights the importance of determining the optimal dosage in a sex-dependent manner to maximize benefits without increasing toxicity before clinical translation. The review provides valuable