Reducing intestinal cholesterol absorption with plant sterol consumption is a well-characterized strategy to lower LDL-C and potentially reduce cardiovascular disease risk. However, over 50 years of clinical research demonstrate that there is significant heterogeneity in the individual LDL-C lowering response to plant sterol therapy. A clear understanding of why plant sterols work effectively in some individuals but not in others will ensure optimal integration of plant sterols in future personalized nutritional lipid-lowering strategies. This review will examine the current knowledge base surrounding the metabolic and genetic determinants of LDL-C lowering in response to plant sterol consumption.