AbstractAtherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality among Western populations. Many risk factors have been identified for ASCVD; however, elevated low‐density lipoprotein cholesterol (LDL‐C) remains the gold standard. Cholesterol metabolism at the cellular and whole‐body level is maintained by an array of interacting components. These regulatory mechanisms have complex behavior. Likewise, the mechanisms which underpin atherogenesis are nontrivial and multifaceted. To help overcome the challenge of investigating these processes mathematical modeling, which is a core constituent of the systems biology paradigm has played a pivotal role in deciphering their dynamics. In so doing models have revealed new insights about the key drivers of ASCVD. The aim of this review is fourfold; to provide an overview of cholesterol metabolism and atherosclerosis, to briefly introduce mathematical approaches used in this field, to critically discuss models of cholesterol metabolism and atherosclerosis, and to highlight areas where mathematical modeling could help to investigate in the future.This article is categorized under: Cardiovascular Diseases > Computational Models