Human factors is a well-established discipline focusing on the fit between human and the environment/technology. Human factors discipline takes a systems-driven approach and focuses on two main outcomes: well-being and performance. Systems thinking is critical in the healthcare domain since it provides a complete perception of the work of a system to better understand all its elements and its outcomes. In this chapter, we discuss how human factors and ergonomics principles contribute to healthcare domain. We provided specific examples especially the use of human factors in health information technology research. We also explained the systems thinking and intersection of systems thinking with human factors perspective and how both of them should be used to explore and study the healthcare systems.