<p>Atherosclerosis is a systemic disease of the arterial tree that often assumes variable forms across vascular territories. As a result, atherosclerotic plaques in different vascular beds differ in frequency, composition, stability and propensity to rupture. Here, we argue that this territorial variability is a manifestation of partially predictable principles. Embryological origin and developmental programming create regionally distinct smooth muscle cell lineages and extracellular matrix architectures, predisposing vascular segments to characteristic modes of injury and repair. Local hemodynamic processes and vessel structures further influence this architecture, leading to distinct atherosclerotic plaque evolution. Microvascular and macrovascular calcification contribute to these processes by amplifying local signals, including inflammation and environmental cues, and by driving the chondrogenic and osteogenic transformation of vascular cells. By synthesizing evidence on divergent atherosclerotic and calcification patterns across vascular beds, the concept of territory-adapted imaging and therapy may improve prevention and risk stratification.</p>