Pediatric cancer survivors have increased risk of obesity, hypertension, dyslipidemia, and type 2 diabetes, leading to premature cardiovascular disease (CVD). Multiple tissues that are involved in glucose homeostasis and lipid metabolism are adversely affected by chemotherapy. This review highlights the relevant tissue and molecular end-organ effects of therapy exposures and synthesizes the current understanding of the mechanisms underlying CVD risk in this vulnerable population. The review also approaches the topic from a developmental perspective, with the goal of providing a translational approach to identifying the antecedents of overt CVD among survivors of pediatric cancer.