Personalized System of Instruction (PSI), also known as the Keller method, is a specific instructional design. There has been limited research focused on how this method has been used in teaching in higher education. The aim of this systematic review is to focus on how PSI has been applied to teaching in higher education in the last 20 years. Searches were conducted on the following databases: Educational Resources Information Center (ERIC), Psychology and Behavioral Sciences Collection (EBSCO), PsycINFO, Scopus and Web of Science. Hand searches were also conducted on a number of journals. Inclusion criteria were that articles (a) included the use of the PSI and (b) included university students as participants. It was found that 27 studies met the inclusion criteria. Studies were divided into themes. Results were discussed in terms of how PSI can be used in teaching and learning, similarities between PSI and other approaches, and the ways PSI could be incorporated with other teaching approaches. Finally, future directions were given for the use of PSI in the area of teaching and learning in higher education.