This chapter describes the discipline of human factors engineering and how it can be specifically applied to the study and improvement of clinical workflow. Human factors engineering is a well-established scientific discipline that studies the functional capabilities and limitations of humans and methods to integrate these findings into the design and optimization of systems, processes and technology. The chapter introduces core concepts and methods from the discipline of human factors engineering and describes how they can be applied to the study and improvement of clinical workflow. Applications include situations where there is a need to understand why performance problems or errors are occurring and what can be done to mitigate them; cases where new Health Information Technology (health IT) is being developed and there is a need to understand work as currently done to insure that the new system will meet the needs of users and effectively support workflow; as well as cases where a new process is introduced and there is a need monitor and manage its impact on user workflow, performance, and satisfaction. The human factors methods presented can be used by a variety of organizations and stake-holders (e.g., technology vendors; clinical organizations, quality and safety departments, and individual researchers) and tailored to the scope, size, and budget of the project. The chapter also covers new developments in how machine learning and artificial intelligence (AI) can play a role, but still needs further study. The chapter will cover considerations in using these advanced technologies, including potential for both improved analytics but also the introduction of new safety concerns, as well as technical and cost considerations when leveraging new methods.