Cardiovascular disease is a leading cause of morbidity and mortality in the Western world. Studies of sortilin’s influence on cardiovascular and metabolic diseases goes far beyond the genome-wide association studies that have revealed an association between cardiovascular diseases and the 1p13 locus that encodes sortilin. Emerging evidence suggests a significant role of sortilin in the pathogenesis of vascular and metabolic diseases; this includes type II diabetes mellitus via regulation of insulin resistance, atherosclerosis through arterial wall inflammation and calcification, and dysregulated lipoprotein metabolism. Sortilin is also known for its functional role in neurological disorders. It serves as a key receptor for cytokines, lipids, and enzymes and participates in pathological cargo loading to and trafficking of extracellular vesicles. This article provides a comprehensive review of sortilin’s contributions to cardiovascular and metabolic diseases but focuses particularly on atherosclerosis. We summarize recent clinical findings that suggest that sortilin may be a cardiovascular risk biomarker and also discuss sortilin as a potential drug target.