The integration of personalized medicine (PM) into mainstream healthcare will only be successful if the public understands and supports this change. The aim was to understand the public perception of the barriers and facilitators towards the use of PM. A systematic review of the literature was conducted within six databases from 2006 to 2018. Twenty-one studies with 9507 participants were included. The key themes were familiarity and willingness to use PM, perceived benefits and perceived risks of PM. The review shows that the public is generally enthusiastic about the introduction of PM, although this should be interpreted with cautious optimism due to participants having a limited familiarity of the underlying principles of PM. The study defines areas where progress can be made to enhance this understanding and addresses legitimate concerns.