The focus of this scoping review paper was to highlight the risks and opportunities associated with the implementation of the Six Sigma methodology (SSM) in the laboratory industry in South Africa (SA), and thereby theoretically establish guidelines for successful implementation. In this review, a total of 43 studies obtained from the two databases, namely Emerald and Google scholar, dated from 2008 to 2021 were used to systematically answer three research questions. The findings showed that organizational leadership commitment or involvement and support is the main key to unlock factors that negatively affect the successful implementation of the SSM.