In today's aging society, more people are living with lifestyle-related noncommunicable diseases (NCDs) such as cardiovascular disease, type 2 diabetes, obesity, and cancer. Numerous opinion-leader organizations recommend lifestyle medicine as the first-line approach in NCD prevention and treatment. However, there is a strong need for a personalized approach as "one-size-fits-all" public health recommendations have been insufficient in addressing the interindividual differences in the diverse populations. Advancement in systems biology and the "omics" technologies has allowed comprehensive analysis of how complex biological systems are impacted upon external perturbations (e.g., nutrition and exercise), and therefore is gradually pushing personalized lifestyle medicine toward reality. Clinicians and healthcare practitioners have a unique opportunity in advocating lifestyle medicine because patients see them as a reliable source of advice. However, there are still numerous technical and logistic challenges to overcome before personal "big data" can be translated into actionable and clinically relevant solutions. Clinicians are also facing various issues prior to bringing personalized lifestyle medicine to their practice. Nevertheless, emerging ground-breaking research projects have given us a glimpse of how systems thinking and computational methods may lead to personalized health advice. It is important that all stakeholders work together to create the needed paradigm shift in healthcare before the rising epidemic of NCDs overwhelm the society, the economy, and the dated health system.