Currently, prevention and treatment of cardiovascular diseases have been on a global focus since it is the number one cause of mortality and morbidity. In the pathogenesis of cardiovascular diseases, it was generally thought that impaired cholesterol homeostasis might be a risk factor. Cholesterol homeostasis is affected by exogenous factors (i.e. diet) and endogenous factors (i.e. certain receptors, enzymes, and transcription factors). In this context, the number of studies investigating the potential mechanisms of dietary fatty acids on cholesterol homeostasis have increased in recent years. As well, cluster of differentiation 36 (CD36) receptor is multifunctional membrane receptor involved in fatty acids uptake, and lipid metabolism, atherothrombosis, and inflammation. The CD36 proposed to be a crucial molecule in cholesterol homeostasis in various mechanisms including absorption/reabsorption, synthesis, and transport of cholesterol and bile acids. Moreover, it was reported that the amount of fatty acids and fatty acid pattern of the diet influenced the CD36 level and CD36 mediated cholesterol metabolism principally in liver, intestine, and macrophages. In these processes, CD36 mediated cholesterol and lipoprotein homeostasis might be impaired from dietary saturated fatty acids (SFA) and trans fatty acids (TFA), whereas ameliorated from monounsaturated fatty acids (MUFA) in diet. The effects of polyunsaturated fatty acids (PUFA) on CD36 mediated cholesterol homeostasis is controversial depending on the amount of n-3 PUFA, n-6 PUFA, and the ratio of n-3/n-6 PUFA. Thus, since CD36 receptor suggested to be a novel nutrient-sensitive biomarker, role of CD36 and dietary fatty acids on cholesterol metabolism might be considered in medical nutrition therapy in near future. Therefore, the novel nutritional target of CD36 and interventions that focus on dietary fatty acids on potential mechanisms underlying cholesterol homeostasis is discussed in this review.