Accumulation of cholesterol in arterial cells, intracellular cholesterol retention, may be responsible for all major manifestations of atherosclerosis on a cellular level. Previously we have shown that intracellular cholesterol retention is the principal event in the genesis of atherosclerotic lesions. This allows us to consider cellular retention of cholesterol as a novel target for anti-atherosclerotic therapy. In this case the target is not the level of blood cholesterol but the level of cholesterol in vascular cells. This review describes our approach based on the use of cultured human arterial cells for the development of direct anti-atherosclerotic therapy. We use natural products as the basis of promising drugs for anti-atherosclerotic therapy. Using natural products, we have developed an approach to prevent intracellular cholesterol retention in cultured cells. Our knowledge of the mechanisms of atherosclerosis is the foundation on which we have developed drugs that have a direct anti-atherosclerotic effect, namely Allicor on the basis of garlic powder, anti-inflammatory drug Inflaminat (calendula, elder, and violet) possessing anti-cytokine activity and phytoestrogen-rich drug Karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid). Treatment with allicor or inflaminat has a direct anti-atherosclerotic effect on carotid atherosclerosis in asymptomatic men. Karinat prevents the development of carotid atherosclerosis in postmenopausal women. Thus, the main findings of our basic research have been successfully translated into clinical practice. As a result, this translation, a novel approach to the development of anti-atherosclerotic therapy, has been established. Our clinical trials have confirmed the suitability of innovative approach and the efficacy of novel drugs developed on the basis our methodology.