The prevalence of obesity in America has reached epidemic proportions, and obesity among women is particularly concerning. Severe obesity (body mass index ≥35 kg m−2) is more prevalent in women than men. Further, women have sex-specific risk factors that must be considered when developing preventive and therapeutic interventions. This review presents personalized medicine as a dynamic approach to obesity prevention, management and treatment for women. First, we review obesity as a complex health issue, with contributing sex-specific, demographic, psychosocial, behavioural, environmental, epigenetic and genetic/genomic risk factors. Second, we present personalized medicine as a rapidly advancing field of health care that seeks to quantify these complex risk factors to develop more targeted and effective strategies that can improve disease management and/or better minimize an individual's likelihood of developing obesity. Third, we discuss how personalized medicine can be applied in a clinical setting with current and emerging tools, including health risk assessments, personalized health plans, and strategies for increasing patient engagement. Finally, we discuss the need for additional research, training and policy that can enhance the practice of personalized medicine in women's obesity, including further advancements in the ‘-omics’ sciences, physician training in personalized medicine, and additional development and standardization of innovative targeted therapies and clinical tools.