Diet is a key modulator of health and disease prevention, with cardiovascular diseases (CVD) a major target. High intakes of saturated fatty acids are linked to increased premature CVD events, the reduction of which has formed the backbone of dietary guidelines to prevent CVD over the past 60 years. However, variable metabolic and health outcomes to SFA reduction, together with outstanding questions regarding replacement macronutrients and food sources of SFA (dairy, meat, plants) have raised controversies over this recommendation. Increased understanding of variation in the physiological response to SFA reduction has potential to impact on the efficacy of this recommendation at a population level. While there is evidence to suggest that personalisation of guidance based on diet, phenotype or genotype is beneficial to health, when tailored advice is offered, individual motivation can become a major challenge. The potential benefits of personalised dietary advise, with a focus on total SFA, foods containing these fats and replacement macronutrients on lipid CVD risk markers and dietary behaviour change will be discussed and possible mechanisms explored.